Mdm2-based modulators of proteolysis and associated methods of use

ABSTRACT

The description relates to MDM2 binding compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the description provides compounds, which contain on one end a ligand which binds to the MDM2 E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional application No.62/191,193, filed Jul. 10, 2015, the entire contents of theaforementioned application are hereby incorporated herein by reference.

INCORPORATION BY REFERENCE

U.S. patent application Ser. No. 14/686,640, filed Apr. 14, 2015,entitled “Imide-Based Modulators of Proteolysis and Associated Methodsof Use”, and PCT Patent Application Serial No. PCT/US2013/021136, filedJan. 11, 2013 entitled “Compounds and Methods for the EnhancedDegradation of Targeted Proteins and Other Polypeptides by an E3Ubiquitin Ligase,” are incorporated herein by reference in theirentirety. Furthermore, all references cited herein are incorporated byreference herein in their entirety.

FIELD OF THE INVENTION

The description provides compounds binding to MDM2, includingbifunctional compounds comprising the same as mentioned, and associatedmethods of use. The bifunctional compounds are useful as modulators oftargeted ubiquitination, especially with respect to a variety ofpolypeptides and other proteins, which are degraded and/or otherwiseinhibited by bifunctional compounds according to the present invention.

BACKGROUND

Most small molecule drugs bind enzymes or receptors in tight andwell-defined pockets. On the other hand, protein-protein interactionsare notoriously difficult to target using small molecules due to theirlarge contact surfaces and the shallow grooves or flat interfacesinvolved. E3 ubiquitin ligases (of which hundreds are known in humans)confer substrate specificity for ubiquitination, and therefore, are moreattractive therapeutic targets than general proteasome inhibitors due totheir specificity for certain protein substrates. The development ofligands of E3 ligases has proven challenging, in part due to the factthat they must disrupt protein-protein interactions. However, recentdevelopments have provided specific ligands which bind to these ligases.For example, since the discovery of Nutlins, the first small molecule E3ligase mouse double minute 2 homolog (MDM2) inhibitors, additionalcompounds have been reported that target MDM2 (i.e., human double minute2 or HDM2) E3 ligases (J. Di, et al. Current Cancer Drug Targets (2011),11(8), 987-994).

Tumor suppressor gene p53 plays an important role in cell growth arrestand apoptosis in response to DNA damage or stress (A. Vazquez, et al.Nat. Rev. Drug. Dis. (2008), 7, 979-982), and inactivation of p53 hasbeen suggested as one of the major pathway for tumor cell survival (A.J. Levine, et al. Nature (2000), 408, 307-310). In cancer patients,about 50% were found with p53 mutation (M. Hollstein, et al. Science(1991), 233, 49-53), while patients with wild type p53 were often foundp53 down regulation by MDM2 through the protein-protein interaction ofp53 and MDM2 (P. Chene, et al. Nat. Rev. Cancer (2003), 3, 102-109).Under normal cell condition without oncogenic stress signal, MDM2 keepsp53 at low concentration. In response to DNA damage or cellular stress,p53 level increases, and that also causes increase in MDM2 due to thefeedback loop from p53/MDM2 auto regulatory system. In other words, p53regulates MDM2 at the transcription level, and MDM2 regulates p53 at itsactivity level (A. J. Levine, et al. Genes Dev. (1993) 7, 1126-1132).

Several mechanisms can explain p53 down regulation by MDM2. First, MDM2binds to N-terminal domain of p53 and blocks expression ofp53-responsive genes (J. Momand, et al. Cell (1992), 69, 1237-1245).Second, MDM2 shuttles p53 from nucleus to cytoplasm to facilitateproteolytic degradation (J. Roth, et al. EMBO J. (1998), 17, 554-564).Lastly, MDM2 carries intrinsic E3 ligase activity of conjugatingubiquitin to p53 for degradation through ubiquitin-dependent 26sproteasome system (UPS) (Y. Haupt, et al. Nature (1997) 387, 296-299).Therefore, disrupting p53/MDM2 auto regulation can restore p53 activityand could bring a new approach in the treatment of cancer. Notsurprisingly, since the first publication of small molecule MDM2inhibitor Nutlins, multiple classes of MDM2 antagonists have beenreported and several of them have advanced to the clinic development (B.Zhang, et al. Future Med. Chem. (2015) 7, 631-645)

The most studied MDM2 antagonists are imidazolines with aromatic ringsdecorated at the three carbons of the ring and NH group functionalized.One example is RG7112 developed by Roche, in which two adjacent phenylrings on imidazoline core are in cis-conformation (L. T. Vassilev, etal. Science (2004) 57, 1454-1472; B. Vu, et al. ACS Med. Chem. Lett.(2013) 4, 466-469). The similar cis-bis-aryl substitution pattern isalso presented in Daiichi-Sankyo's MDM2 antagonist DS-5272, althoughimidazoline core was replaced with thiazoloimidazoline (M. Miyazaki, etal. Bioorg. Med. Chem. Lett. (2015) 23, 2360-2367; WO 2014/038606). Theearlier version DS-3032b advanced to clinical testing(www.clinicaltrials.gov)

The spiroindolinone compounds MI-219 and MI-888 from University ofMichigan possesses a 5-membered pyrrolidine ring with two adjacentphenyl ring substituted at the core with cis- and trans-conformation (S.Wang, et al. PNAS USA (2008) 105, 3933-3938). Further modification inthis chemical class resulted in Sanofi-Aventis' SAR405838 (S. Wang, etal. J. Med. Chem. (2015) 58, 1038-1052; WO 2014/107713).

Similar to spiroindolinone MDM2 antagonist, non-spiro molecules withpyrrolidine core decorated by adjacent trans-bis-aryl rings werereported by Roche, and RG7388 from this chemical series became Roche'ssecond MDM2 inhibitor in the clinic (Q. Ding, et al. J. Med. Chem.(2013) 56, 5979-5983)

Piperidinone and morpholinone cores with adjacent trans-arylsubstitution on the core are another chemical class of MDM2 inhibitorsreported by Amgen. These compounds are structurally different fromimidazoline or spiro-indolinone or pyrrolidine chemical class. AMG-232with a piperidinone core advanced to the clinic (D. Sun, et al. J. Med.Chem. (2014) 57, 1454-1472). AM-7209 is a more potent molecule fromAmgen reported recently (Y. Rew, et al. J. Med. Chem. (2014) 57,10499-10511). A diversity of structures with 6-membered cores werereported by Amgen (WO 2014/151863, WO2014/134201, US 2014/235629, US2014/0243372).

Pyrrolopyrimidine- and imidazolopyridine-derived carboxylic acid andacid mimetic oxadiazolone analogs are potent HDM2 inhibitors reported byMerck (WO 2014/100065; WO 2014/100071). MK-8242, also known as SCH90042,has been tested in the clinic (www.clinicaltrials.gov).

Novartis reported pyrrolopyrrolidinone chemical class where three arylgroups were attached to pyrrolopyrrolidinone core (WO 2013/175417).CMG097, also known as NVP-CMG-097 in the clinic, is a small moleculeMDM2 inhibitor derived from 1,2-bis-aryl-substituteddihydro-isoquinolinone chemical class (WO 2014/020502).

All small molecule MDM2 inhibitors mentioned above showed potentactivity in inhibiting p53 and MDM2 interaction, which consequentlystabilizes p53. However, due to the feedback loop, antagonism mode alsoresulted in MDM2 up-regulation at the transcription level as shown inthe literature. As such, the potential exists that degrading MDM2 couldovercome issues associated with MDM2 up-regulation. Also, because MDM2functions as E3 ligase, recruiting MDM2 to a disease causing protein andeffectuating its ubiquitination and degradation is an approach of highinterest for drug discovery.

An ongoing need exists in the art for effective treatments for disease,especially hyperplasias and cancers. However, non-specific effects, andthe inability to target and modulate certain classes of proteinsaltogether, such as transcription factors, remain as obstacles to thedevelopment of effective anti-cancer agents. As such, small moleculetherapeutic agents that leverage or potentiate MDM2 substratespecificity and, at the same time, are “tunable” such that a wide rangeof protein classes can be targeted and modulated with specificity wouldbe very useful as a therapeutic.

SUMMARY

The present disclosure describes bifunctional compounds which functionto recruit endogenous proteins to an E3 ubiquitin ligase fordegradation, and methods of using the same. In particular, the presentdisclosure provides bifunctional or proteolysis targeting chimeric(PROTAC) compounds, which find utility as modulators of targetedubiquitination of a variety of polypeptides and other proteins, whichare then degraded and/or otherwise inhibited by the bifunctionalcompounds as described herein. An advantage of the compounds providedherein is that a broad range of pharmacological activities is possible,consistent with the degradation/inhibition of targeted polypeptides fromvirtually any protein class or family. In addition, the descriptionprovides methods of using an effective amount of the compounds asdescribed herein for the treatment or amelioration of a diseasecondition, such as cancer, e.g., multiple myeloma.

As such, in one aspect the disclosure provides MDM2 ligand-based PROTACcompounds of Formula (A):

Formula (A) represents bifunctional or PROTAC compounds, which comprisean E3 ubiquitin ligase binding moiety (i.e., a ligand for an E3 ubquitinligase or “ULM” group), coupled via linker (L) to a moiety that binds atarget protein (i.e., a protein/polypeptide targeting ligand or “PTM”group) such that the target protein/polypeptide is placed in proximityto the ubiquitin ligase to effect degradation (and inhibition) of thatprotein. In a preferred embodiment, the ULM is a moiety that binds MDM2E3 ubiquitin ligase (i.e., “MLM”).

In Formula (A), the respective positions of the PTM and MLM moieties aswell as their number as illustrated herein is provided by way of exampleonly and is not intended to limit the compounds in any way. As would beunderstood by the skilled artisan, the bifunctional compounds asdescribed herein can be synthesized such that the number and position ofthe respective functional moieties can be varied as desired.

In certain preferred embodiments, PTM is a protein target moiety. Assuch, PTM binds to a specific protein which is set to be ubiquitinatedor degraded.

In certain embodiments, “L” is the linker that connects PTM and MLM. Incertain embodiments, L is a bond (i.e., absent). In certain additionalembodiments, L is a chemical linker as described herein. In certainpreferred embodiments, the linker “L” is a connector with a linearnon-hydrogen atom number in the range of 1 to 20. The connector “L” cancontain, but not limited to the functional groups such as ether, amide,alkane, alkene, alkyne, ketone, hydroxyl, carboxylic acid, thioether,sulfoxide, and sulfone. The linker can contain aromatic, heteroaromatic,cyclic, bicyclic and tricyclic moieties. Substitution with halogen, suchas Cl, F, Br and I can be included in the linker. In the case offluorine substitution, single or multiple fluorines can be included.

In certain additional embodiments, the MLM of the bifunctional compoundwith a formula (A) comprises chemical moieties such as substitutedimidazolines, substituted spiro-indolinones, substituted pyrrolidines,substituted piperidinones, substituted morpholinones, substitutedpyrrolopyrimidines, substituted imidazolopyridines, substitutedthiazoloimidazoline, substituted pyrrolopyrrolidinones, and substitutedisoquinolinones.

In additional embodiments, the MLM comprises the core structuresmentioned above with adjacent bis-aryl substitutions positioned as cis-or trans-configurations.

In still additional embodiments, the MLM comprises part of structuralfeatures as in RG7112, RG7388, SAR405838, AMG-232, AM-7209, DS-5272,MK-8242, and NVP-CGM-097, and analogs or derivatives thereof.

In certain embodiments, the compounds as described herein comprisemultiple MLMs, multiple PTMs, multiple chemical linkers or a combinationthereof.

In certain embodiments, PTMs can be, but not limited to, small moleculesbinding to kinases, enzymes, transporters, nuclear hormone receptors,non-nuclear hormone receptors, G-protein coupled receptors (GPCRs),transcription factors, and epigenetic targets.

In certain embodiments, the epigenetic targets can be bromodomain andextra terminal domain (BET) family proteins, such as, e.g., BRD1, -2,-3, or -4.

In certain embodiments, the nuclear hormone receptors can be, but notlimited to, androgen receptor (AR) and estrogen receptor (ER).

In another aspect, the description provides bifunctional molecules asshows in Formula (B), wherein PTM comprises an MDM2 binding moiety (MBM)coupled via a linker (L) to ULM (ubiquitination ligase binding moiety),which comprises a moiety that binds an E3 ubiquitin ligase, e.g., VonHippel-Lindau E3 ubiquitin ligase (VHM), Cereblon (CLM) or MDM2 (MLM).

In certain embodiments, “L” is the linker that connects PTM and MLM. Incertain embodiments, L is a bond (i.e., absent). In certain additionalembodiments, L is a chemical linker as described herein. In certainpreferred embodiments, the linker “L” is a connector with a linearnon-hydrogen atom number in the range of 1 to 20. The connector “L” cancontain, but not limited to the functional groups such as ether, amide,alkane, alkene, alkyne, ketone, hydroxyl, carboxylic acid, thioether,sulfoxide, and sulfone. The linker can contain aromatic, heteroaromatic,cyclic, bicyclic and tricyclic moieties. Substitution with halogen, suchas Cl, F, Br and I can be included in the linker. In the case offluorine substitution, single or multiple fluorines can be included.

In an embodiment, VLM can be hydroxyproline or a derivative thereof.Other contemplated VLMs are described in U.S. Patent Application Pub.No. 2014/03022523A1, and 2015/0291562A1, which are incorporated hereinin their entirety.

In certain embodiments, MBM comprises chemical moieties such assubstituted imidazolines, substituted spiro-indolinones, substitutedpyrrolidines, substituted piperidinones, substituted morpholinones,substituted pyrrolopyrimidines, substituted imidazolopyridines,substituted thiazoloimidazoline, substituted pyrrolopyrrolidinones, andsubstituted isoquinolinones.

In additional embodiments, the MBM comprises the core structuresmentioned above with adjacent bis-aryl substitutions positioned as cis-or trans-configurations.

In still additional embodiments, the MBM comprises part of structuralfeatures as in RG7112, RG7388, SAR405838, AMG-232, AM-7209, DS-5272,MK-8242, and NVP-CGM-097, and analogs or derivatives thereof.

In certain embodiments, VLM is a derivative of trans-3-hydroxyproline,where both nitrogen and carboxylic acid in trans-3-hydroxyproline arefunctionalized as amides.

In certain embodiments, CLM is a derivative of piperidine-2,6-dione,where piperidine-2,6-dione can be substituted at the 3-position, and the3-substitution can be bicyclic hetero-aromatics with the linkage as C—Nbond or C—C bond. Examples of CLM can be, but not limited to,pomalidomide, lenalidomide and thalidomide and their derivatives

In an additional aspect, the description provides therapeuticcompositions comprising an effective amount of a compound as describedherein or salt form thereof, and a pharmaceutically acceptable carrier.The therapeutic compositions modulate protein degradation in a patientor subject, for example, an animal such as a human, and can be used fortreating or ameliorating disease states or conditions which aremodulated through the degraded protein. In certain embodiments, thetherapeutic compositions as described herein may be used to effectuatethe degradation of proteins of interest for the treatment oramelioration of a disease, e.g., cancer.

In yet another aspect, the description provides a method ofubiquitinating/degrading a target protein in a cell. In certainembodiments, the method comprises administering to a subject orcontacting a subject, e.g., a patient or a cell, with a bifunctionalcompound as described herein, wherein the bifunctional compoundeffectuates degradation of the target protein. Degradation of the targetprotein will occur when the target protein is placed in proximity to theubiquitin ligase, thus resulting in degradation/inhibition of theeffects of the target protein and the control of protein levels. Thecontrol of protein levels provides treatment of a disease state orcondition, which is modulated through the target protein by lowering thelevel of that protein in the cells of a patient.

In still another aspect, the description provides methods for treatingor emeliorating a disease, disorder or symptom thereof in a subject or apatient, e.g., an animal such as a mammal or a human, comprisingadministering to a subject in need thereof a composition comprising aneffective amount, e.g., a therapeutically effective amount, of acompound as described herein or salt form thereof, and apharmaceutically acceptable carrier, wherein the composition iseffective for treating or ameliorating the disease or disorder orsymptom thereof in the subject.

In another aspect, the description provides methods for identifying theeffects of the degradation of proteins of interest in a biologicalsystem using compounds according to the present invention.

The preceding general areas of utility are given by way of example onlyand are not intended to be limiting on the scope of the presentdisclosure and appended claims. Additional objects and advantagesassociated with the compositions, methods, and processes of the presentinvention will be appreciated by one of ordinary skill in the art inlight of the instant claims, description, and examples. For example, thevarious aspects and embodiments of the invention may be utilized innumerous combinations, all of which are expressly contemplated by thepresent description. These additional advantages objects and embodimentsare expressly included within the scope of the present invention. Thepublications and other materials used herein to illuminate thebackground of the invention, and in particular cases, to provideadditional details respecting the practice, are incorporated byreference.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated into and form a partof the specification, illustrate several embodiments of the presentinvention and, together with the description, serve to explain theprinciples of the invention. The drawings are only for the purpose ofillustrating an embodiment of the invention and are not to be construedas limiting the invention. Further objects, features and advantages ofthe invention will become apparent from the following detaileddescription taken in conjunction with the accompanying figures showingillustrative embodiments of the invention, in which:

FIG. 1: c-Myc suppression in 22rv1 cells by chimeric molecules, whereBRD4 ligand is connected through linkers to MDM2 ligands using partialstructural motif in RG7388. Chimeric molecules with inactive MDM2 ligand(enantiomer of the active counterpart) demonstrated no c-Myc suppressionacross a range of concentrations, while chimeric molecules with activeMDM2 ligand showed dose dependent c-Myc suppression, suggesting BRD4degradation mediated by MDM2 E3 ligase ubiquitination mechanism, asc-Myc is directly regulated by the level of BRD4. Chimeric moleculeswith MDM2 ligand as a racemate displayed similar c-Myc suppression asobserved in those containing active MDM2 ligand.

FIG. 2: Western blot of HCT116 cells treated with chimeric molecules,where BRD4 ligand is connected through linkers to MDM2 ligands usingpartial structural motif in RG7388. Chimeric molecules with inactiveMDM2 ligand (A-1891, A-1894) demonstrated no p53 level increase and noMDM2 up-regulation, while chimeric molecules with active MDM2 ligand(A-1864, A1892 and A-1893, A-1877 carried a racemic MDM2 binding ligand)showed dose dependent p53 level increase and up-regulation of MDM2,suggesting chimeric molecules with BRD4 binding fragment and MDM2binding fragment connected through a linker can function as smallmolecule MDM2 antagonist in stabilizing p53. The less significant MDM2up regulation and p53 level increase is due to the chimeric moleculeaction mechanism of not only binding to MDM2 to block p53-MDM2interaction but also degrading MDM2. Therefore, the net MDM2up-regulation is significantly less, which also translated to p53 leveldue to MDM2-p53 feedback loop.

FIG. 3: Western blot of HCT116 cells treated with chimeric molecules,where MDM2 ligand (using partial structural motif of RG7388) isconnected through linkers to VHL ligand. Chimeric molecules withinactive MDM2 ligand (A-1897, A1908, and A-1911) demonstrated no p53level increase and no MDM2 up-regulation, while chimeric molecules withactive MDM2 ligand (A-1896, A-1907, and A-1910, with A-1877, A-1895, andA-1909 carrying a racemic MDM2 binding ligand) showed dose dependent p53level increase.

FIG. 4: Inhibition of cell proliferation in HCT116 and 22rv1 cells bychimeric molecules containing MDM2 binding motif. In p53^(WT) HCT-116colon cancer cell lines, MDM2-recruiting BRD-4 PROTAC with active MDM2binding moiety (A-1893) caused very potent growth inhibition incomparison with the MDM2-recruiting BRD-4 PROTAC with inactive MDM2binding moiety (A-1894). In this cell growth assay, BRD4-Cereblon PROTACA-825, MDM2 antagonist RG7388 (A-1850), the racemate of RG7388 (A-1851)and JQ1 were included as a direct comparison.

FIG. 5: Time course of BRD4 degradation caused by BRD4-MDM2 chimericcompound (A-1893) in human colon cancer cell line HCT116.

FIG. 6: Time course of BRD4 degradation caused by BRD4-MDM2 chimericcompound (A-1893) in human lung cancer cell line A549.

DETAILED DESCRIPTION

The following is a detailed description provided to aid those skilled inthe art in practicing the present invention. Those of ordinary skill inthe art may make modifications and variations in the embodimentsdescribed herein without departing from the spirit or scope of thepresent disclosure. All publications, patent applications, patents,figures and other references mentioned herein are expressly incorporatedby reference in their entirety.

The present disclosure describes bifunctional compounds which functionto recruit endogenous proteins to an E3 ubiquitin ligase fordegradation, and methods of using the same. In particular, the presentdisclosure provides bifunctional or proteolysis targeting chimeric(PROTAC) compounds, which find utility as modulators of targetedubiquitination of a variety of polypeptides and other proteins, whichare then degraded and/or otherwise inhibited by the bifunctionalcompounds as described herein. An advantage of the compounds providedherein is that a broad range of pharmacological activities is possible,consistent with the degradation/inhibition of targeted polypeptides fromvirtually any protein class or family.

As such, presently described are compositions and methods that relate tothe surprising and unexpected discovery that an E3 ubiquitin ligaseprotein, e.g., MDM2, ubiquitinates a target protein once it and thetarget protein are placed in proximity by a bifunctional or chimericconstruct (e.g., a PROTAC) that binds the E3 ubiquitin ligase proteinand the target protein. Accordingly, the present invention provides suchcompounds and compositions comprising an E3 ubiquintin ligase bindingmoiety (“ULM”) coupled to a protein target binding moiety (“PTM”), whichresult in the ubiquitination of a chosen target protein, which leads todegradation of the target protein by the proteasome. The presentinvention also provides a library of compositions and the use thereof.

In particular, the present application is directed to compounds whichcontain a ligand, e.g., a small molecule ligand (i.e., having amolecular weight of below 2,000, 1,000, 500, or 200 Daltons), which iscapable of binding to a ubiquitin ligase, such as MDM2, and a moietythat is capable of binding to a target protein, in such a way that thetarget protein is placed in proximity to the ubiquitin ligase to effectdegradation (and/or inhibition) of that protein.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. The terminology used in thedescription is for describing particular embodiments only and is notintended to be limiting of the invention.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise (such as in the case of a groupcontaining a number of carbon atoms in which case each carbon atomnumber falling within the range is provided), between the upper andlower limit of that range and any other stated or intervening value inthat stated range is encompassed within the invention. The upper andlower limits of these smaller ranges may independently be included inthe smaller ranges is also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either bothof those included limits are also included in the invention.

The following terms are used to describe the present invention. Ininstances where a term is not specifically defined herein, that term isgiven an art-recognized meaning by those of ordinary skill applying thatterm in context to its use in describing the present invention.

The articles “a” and “an” as used herein and in the appended claims areused herein to refer to one or to more than one (i.e., to at least one)of the grammatical object of the article unless the context clearlyindicates otherwise. By way of example, “an element” means one elementor more than one element.

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases. Multiple elements listed with“and/or” should be construed in the same fashion, i.e., “one or more” ofthe elements so conjoined. Other elements may optionally be presentother than the elements specifically identified by the “and/or” clause,whether related or unrelated to those elements specifically identified.Thus, as a non-limiting example, a reference to “A and/or B”, when usedin conjunction with open-ended language such as “comprising” can refer,in one embodiment, to A only (optionally including elements other thanB); in another embodiment, to B only (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification and in the claims, “or” should beunderstood to have the same meaning as “and/or” as defined above. Forexample, when separating items in a list, “or” or “and/or” shall beinterpreted as being inclusive, i.e., the inclusion of at least one, butalso including more than one, of a number or list of elements, and,optionally, additional unlisted items. Only terms clearly indicated tothe contrary, such as “only one of” or “exactly one of,” or, when usedin the claims, “consisting of,” will refer to the inclusion of exactlyone element of a number or list of elements. In general, the term “or”as used herein shall only be interpreted as indicating exclusivealternatives (i.e., “one or the other but not both”) when preceded byterms of exclusivity, such as “either,” “one of,” “only one of,” or“exactly one of.”

In the claims, as well as in the specification above, all transitionalphrases such as “comprising,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” “composed of,” and the like are tobe understood to be open-ended, i.e., to mean including but not limitedto. Only the transitional phrases “consisting of” and “consistingessentially of” shall be closed or semi-closed transitional phrases,respectively, as set forth in the United States Patent Office Manual ofPatent Examining Procedures, Section 2111.03.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from anyone or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anon-limiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

It should also be understood that, in certain methods described hereinthat include more than one step or act, the order of the steps or actsof the method is not necessarily limited to the order in which the stepsor acts of the method are recited unless the context indicatesotherwise.

The terms “co-administration” and “co-administering” or “combinationtherapy” refer to both concurrent administration (administration of twoor more therapeutic agents at the same time) and time variedadministration (administration of one or more therapeutic agents at atime different from that of the administration of an additionaltherapeutic agent or agents), as long as the therapeutic agents arepresent in the patient to some extent, preferably at effective amounts,at the same time. In certain preferred aspects, one or more of thepresent compounds described herein, are co-administered in combinationwith at least one additional bioactive agent, especially including ananticancer agent. In particularly preferred aspects, theco-administration of compounds results in synergistic activity and/ortherapy, including anticancer activity.

The term “compound”, as used herein, unless otherwise indicated, refersto any specific chemical compound disclosed herein and includestautomers, regioisomers, geometric isomers, and where applicable,stereoisomers, including optical isomers (enantiomers) and othersteroisomers (diastereomers) thereof, as well as pharmaceuticallyacceptable salts and derivatives (including prodrug forms) thereof whereapplicable, in context. Within its use in context, the term compoundgenerally refers to a single compound, but also may include othercompounds such as stereoisomers, regioisomers and/or optical isomers(including racemic mixtures) as well as specific enantiomers orenantiomerically enriched mixtures of disclosed compounds. The term alsorefers, in context to prodrug forms of compounds which have beenmodified to facilitate the administration and delivery of compounds to asite of activity. It is noted that in describing the present compounds,numerous substituents and variables associated with same, among others,are described. It is understood by those of ordinary skill thatmolecules which are described herein are stable compounds as generallydescribed hereunder. When the bond is shown, both a double bond andsingle bond are represented within the context of the compound shown.

The term “compound” or “chemical compound” as used herein can includeorganometallic compounds, organic compounds, metals, transitional metalcomplexes, and small molecules. In certain preferred embodiments,polynucleotides are excluded from the definition of compounds. In otherpreferred embodiments, polynucleotides and peptides are excluded fromthe definition of compounds. In a particularly preferred embodiment, theterm compounds refers to small molecules (e.g., preferably, non-peptidicand non-oligomeric) and excludes peptides, polynucleotides, transitionmetal complexes, metals, and organometallic compounds.

As used herein, the term “small molecule” refers to a non-peptidic,non-oligomeric organic compound either synthesized in the laboratory orfound in nature. Small molecules, as used herein, can refer to compoundsthat are “natural product-like”, however, the term “small molecule” isnot limited to “natural product-like” compounds. Rather, a smallmolecule is typically characterized in that it contains severalcarbon-carbon bonds, and has a molecular weight of less than 2000 g/mol,preferably less than 1500 g/mol, although this characterization is notintended to be limiting for the purposes of the present application. Incertain other preferred embodiments, synthetic small molecules areutilized.

The term “ubiquitin ligase” refers to a family of proteins thatfacilitate the transfer of ubiquitin to a specific substrate protein,targeting the substrate protein for degradation. For example, MDM2 is anE3 ubiquitin ligase protein that alone or in combination with an E2ubiquitin-conjugating enzyme causes the attachment of ubiquitin to alysine on a target protein, and subsequently targets the specificprotein substrates for degradation by the proteasome. Thus, E3 ubiquitinligase alone or in complex with an E2 ubiquitin conjugating enzyme isresponsible for the transfer of ubiquitin to targeted proteins. Ingeneral, the ubiquitin ligase is involved in polyubiquitination suchthat a second ubiquitin is attached to the first; a third is attached tothe second, and so forth. Polyubiquitination marks proteins fordegradation by the proteasome. However, there are some ubiquitinationevents that are limited to mono-ubiquitination, in which only a singleubiquitin is added by the ubiquitin ligase to a substrate molecule. Themost common lysine is Lys48 on the ubiquitin chain. This is the lysineused to make polyubiquitin, which is recognized by the proteasome.

The term “patient” or “subject” is used throughout the specification todescribe an animal, preferably a human or a domesticated animal, to whomtreatment, including prophylactic treatment, with the compositionsaccording to the present invention is provided. For treatment of thoseinfections, conditions or disease states which are specific for aspecific animal such as a human patient, the term patient refers to thatspecific animal, including a domesticated animal such as a dog or cat ora farm animal such as a horse, cow, sheep, etc. In general, in thepresent invention, the term patient refers to a human patient unlessotherwise stated or implied from the context of the use of the term.

The term “effective” is used to describe an amount of a compound,composition or component which, when used within the context of itsintended use, effects an intended result. The term effective subsumesall other effective amount or effective concentration terms, which areotherwise described or used in the present application.

DETAILED DESCRIPTION

In one aspect, the description provides compounds comprising an MDM2 E3ubiquitin ligase binding moiety (MLM) connected to a linker (L), asshown below, wherein MLM is a ligand for MDM2 or HDM2, and L is a bondor a chemical linker group.

The number and/or relative positions of the moieties in the compoundsillustrated herein are provided by way of example only. As would beunderstood by the skilled artisan, compounds as described herein can besynthesized with any desired number and/or relative position of therespective functional moieties.

In another aspect, the description provides compounds comprising an MDM2E3 ubiquitin ligase binding moiety (MLM) coupled via a linker (L) to aprotein targeting moiety (PTM), wherein L is a bond or a chemical linkergroup. These compounds are described herein as “MDM2 PROTAC compounds”(MDM2-mediated proteolysis targeting chimerics) and are presented asFormula (A):

In Formula (A), the respective positions of the PTM and MLM moieties aswell as their number as illustrated herein is provided by way of exampleonly and is not intended to limit the compounds in any way. As would beunderstood by the skilled artisan, the bifunctional compounds asdescribed herein can be synthesized such that the number and position ofthe respective functional moieties can be varied as desired.

In Formula (A), PTM is a protein/polypeptide targeting moiety, L is alinker, and MLM is a MDM2 E3 ubiquitin ligase binding moiety.

In another aspect, the description provides bifunctional molecules asshows in Formula (B), wherein PTM comprises an MDM2 binding moiety (MBM)coupled via a linker (L) to ULM (ubiquitination ligase binding moiety),which comprises a moiety that binds an E3 ubiquitin ligase, e.g., VonHippel Lindau E3 Ligase (VHM), Cereblon (CLM) or MDM2 (MLM).

The terms ULM is used inclusively unless the context indicates otherwiseto indicate an E3 ubiquitin ligase binding moiety, including those thatbind MDM2 (i.e., MLMs). Further, the term MLM is inclusive of allpossible MDM2 E3 ubiquitin ligase binding moieties.

In certain embodiments, the E3 ubiquitin ligase is MDM2. As such, theULM is an MLM that binds to MDM2.

In certain preferred embodiments, PTM is a protein target moiety. Assuch, PTM binds to a specific protein which is set to be ubiquitinatedor degraded.

In certain preferred embodiments, “L” is a linker, e.g., a bond (i.e.,absent) or a chemical linker that connects PTM and MLM.

In certain additional embodiments, the MLM of the bifunctional compoundas depicted in Formula (A) or (B) comprises chemical moieties such assubstituted imidazolines, substituted spiro-indolinones, substitutedpyrrolidines, substituted piperidinones, substituted morpholinones,substituted pyrrolopyrimidines, substituted imidazolopyridines,substituted thiazoloimidazoline, substituted pyrrolopyrrolidinones, andsubstituted isoquinolinones.

In additional embodiments, the MLM comprises the core structuresmentioned above with adjacent bis-aryl substitutions positioned as cis-or trans-configurations.

In still additional embodiments, the MLM comprises part of structuralfeatures as in RG7112, RG7388, SAR405838, AMG-232, AM-7209, DS-5272,MK-8242, and NVP-CGM-097, and analogs or derivatives thereof.

In certain embodiments, the linker “L” is a connector with a linearnon-hydrogen atom number in the range of 1 to 20. In additionalembodiments, the connector “L” comprises a functional group, e.g., anether, amide, alkane, alkene, alkyne, ketone, hydroxyl, carboxylic acid,thioether, sulfoxide, and sulfone. The linker can also comprisearomatic, heteroaromatic, cyclic, bycyclic and tricyclic moieties.Substitution with halogen, such as Cl, F, Br and I can be included inthe linker. In the case of fluorine substitution, single or multiplefluorines can be included.

In certain embodiments, the compounds as described herein comprisemultiple MLMs, multiple PTMs, multiple chemical linkers or a combinationthereof.

In certain embodiments, PTMs can be, but not limited to, small moleculesbinding to kinases, enzymes, transporters, nuclear hormone receptors,non-nuclear hormone receptors, G-protein coupled receptors (GPCRs),transcription factors, and epigenetic targets.

In certain embodiments, PTM is a small molecule binding to epigenetictargets, and the epigenetic targets can be BRDs, such as BRD4.

In certain embodiments, PTM is a small molecule binding to nuclearhormone receptors, and the nuclear hormone receptor can be, but notlimited to, androgen receptor (AR) and estrogen receptor (ER).

In additional embodiments, the description provides the compounds asdescribed herein including their enantiomers, diastereomers, solvatesand polymorphs, including pharmaceutically acceptable salt formsthereof, e.g., acid and base salt forms.

In certain preferred embodiments, MLM is a derivative of substitutedimidazoline represented as Formula (A-1), or thiazoloimidazolinerepresented as Formula (A-2), or spiro indolinone represented as Formula(A-3), or pyrollidine represented as Formula (A-4), orpiperidinone/morphlinone represented as Formula (A-5), or isoquinolinonerepresented as Formula (A-6), or pyrollopyrimidine/imidazolopyridinerepresented as Formula (A-7), orpyrrolopyrrolidinone/imidazolopyrrolidinone represented as Formula(A-8).

wherein above Formula (A-1) through Formula (A-8),X is selected from the group consisting of carbon, oxygen, sulfur,sulfoxide, sulfone, and N—R^(a);

-   -   R^(a) is independently H or an alkyl group with carbon number 1        to 6;        Y and Z are independently carbon or nitrogen;        A, A′ and A″ are independently selected from C, N, O or S, can        also be one or two atoms forming a fused bycyclic ring, or a        6,5- and 5,5-fused aromatic bicyclic group;        R₁, R₂ are independently selected from the group consisting of        an aryl or heteroaryl group, a heteroaryl group having one or        two heteroatoms independently selected from sulfur or nitrogen,        wherein the aryl or heteroaryl group can be mono-cyclic or        bi-cyclic, or unsubstituted or substituted with one to three        substituents independently selected from the group consisting        of:    -   halogen, —CN, C1 to C6 alkyl group, C3 to C6 cycloalkyl, —OH,        alkoxy with 1 to 6 carbons, fluorine substituted alkoxy with 1        to 6 carbons, sulfoxide with 1 to 6 carbons, sulfone with 1 to 6        carbons, ketone with 2 to 6 carbons, amides with 2 to 6 carbons,        and dialkyl amine with 2 to 6 carbons;        R₃, R₄ are independently selected from the group consisting of        H, methyl and C1 to C6 alkyl;        R₅ is selected from the group consisting of an aryl or        heteroaryl group, a heteroaryl group having one or two        heteroatoms independently selected from sulfur or nitrogen,        wherein the aryl or heteroaryl group can be mono-cyclic or        bi-cyclic, or unsubstituted or substituted with one to three        substituents independently selected from the group consisting        of:    -   halogen, —CN, C1 to C6 alkyl group, C3 to C6 cycloalkyl, —OH,        alkoxy with 1 to 6 carbons, fluorine substituted alkoxy with 1        to 6 carbons, sulfoxide with 1 to 6 carbons, sulfone with 1 to 6        carbons, ketone with 2 to 6 carbons, amides with 2 to 6 carbons,        dialkyl amine with 2 to 6 carbons, alkyl ether (C2 to C6), alkyl        ketone (C3 to C6), morpholinyl, alkyl ester (C3 to C6), alkyl        cyanide (C3 to C6);        R₆ is H or —C(═O)R^(b), wherein    -   R^(b) is selected from the group consisting of alkyl,        cycloalkyl, mono-, di- or tri-substituted aryl or heteroaryl,        4-morpholinyl, 1-(3-oxopiperazunyl), 1-piperidinyl,        4-N—R^(c)-morpholinyl, 4-R^(c)-1-piperidinyl, and        3-R^(c)-1-piperidinyl, wherein    -   R^(c) is selected from the group consisting of alkyl, fluorine        substituted alkyl, cyano alkyl, hydroxyl-substituted alkyl,        cycloalkyl, alkoxyalkyl, amide alkyl, alkyl sulfone, alkyl        sulfoxide, alkyl amide, aryl, heteroaryl, mono-, bis- and        tri-substituted aryl or heteroaryl, CH2CH2R^(d), and        CH2CH2CH2R^(d), wherein    -   R^(d) is selected from the group consisting of alkoxy, alkyl        sulfone, alkyl sulfoxide, N-substituted carboxamide,        —NHC(O)-alkyl, —NH—SO₂-alkyl, aryl, substituted aryl,        heteroaryl, substituted heteroaryl;        R₇ is selected from the group consisting of H, C1 to C6 alkyl,        cyclic alkyl, fluorine substituted alkyl, cyano substituted        alkyl, 5- or 6-membered hetero aryl or aryl, substituted 5- or        6-membered hetero aryl or aryl;        R₈ is selected from the group consisting of —R^(e)—C(O)—R^(f),        —R^(e)-alkoxy, —R^(e)-aryl, —R^(e)-heteroaryl, and        —R^(e)—C(O)—R^(f)—C(O)—R^(g), wherein:    -   R^(e) is an alkylene with 1 to 6 carbons, or a bond;    -   R^(f) is a substituted 4- to 7-membered heterocycle;    -   R^(g) is selected from the group consisting of aryl, hetero        aryl, substituted aryl or heteroaryl, and 4- to 7-membered        heterocycle;        R₉ is selected from the group consisting of a mono-, bis- or        tri-substituent on the fused bicyclic aromatic ring in Formula        (A-3), wherein the substitutents are independently selected from        the group consistin of halogen, alkene, alkyne, alkyl,        unsubstituted or substituted with Cl or F;        R₁₀ is selected from the group consistin of an aryl or        heteroaryl group, wherein the heteroaryl group can contain one        or two heteroatoms as sulfur or nitrogen, aryl or heteroaryl        group can be mono-cyclic or bi-cyclic, the aryl or heteroaryl        group can be unsubstituted or substituted with one to three        substituents, including a halogen, F, Cl, —CN, alkene, alkyne,        C1 to C6 alkyl group, C1 to C6 cycloalkyl, —OH, alkoxy with 1 to        6 carbons, fluorine substituted alkoxy with 1 to 6 carbons,        sulfoxide with 1 to 6 carbons, sulfone with 1 to 6 carbons,        ketone with 2 to 6 carbons;        R₁₁ is —C(O)—N(R^(h))(R^(i)), wherein R^(h) and R^(i) are        selected from groups consisting of the following:    -   H, C1 to C6 alkyl, alkoxy substituted alkyl, sulfone substituted        alkyl, aryl, heterol aryl, mono-, bis- or tri-substituted aryl        or hetero aryl, alkyl carboxylic acid, heteroaryl carboxylic        acid, alkyl carboxylic acid, fluorine substituted alkyl        carboxylic acid, aryl substituted cycloalkyl, hetero aryl        substituted cycloalkyl; wherein    -   R^(h) and R^(i) are independently selected from the group        consisting of H, connected to form a ring,        4-hydroxycyclohehexane; mono- and di-hydroxy substituted alkyl        (C3 to C6); 3-hydroxycyclobutane; phenyl-4-carboxylic acid, and        substituted phenyl-4-carboxylic acid;        R₁₂ and R₁₃ are independently selected from H, lower alkyl (C1        to C6), lower alkenyl (C2 to C6), lower alkynyl (C2 to C6),        cycloalkyl (4, 5 and 6-membered ring), substituted cycloalkyl,        cycloalkenyl, substituted cycloalkenyl, 5- and 6-membered aryl        and heteroaryl, R12 and R13 can be connected to form a 5- and        6-membered ring with or without substitution on the ring;        R₁₄ is selected from the group consisting of alkyl, substituted        alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, heterocycle, substituted        heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl        and substituted cycloalkenyl;

R₁₅ is CN;

R₁₆ is selected from the group consisting of C1-6 alkyl, C1-6cycloalkyl, C2-6 alkenyl, C1-6 alkyl or C3-6 cycloalkyl with one ormultiple hydrogens replaced by fluorine, alkyl or cycloalkyl with oneCH₂ replaced by S(═O), —S, or —S(═O)₂, alkyl or cycloalkyl with terminalCH₃ replaced by S(═O)₂N(alkyl)(alkyl), —C(═O)N(alkyl)(alkyl),—N(alkyl)S(═O)₂(alkyl), —C(═O)2(allkyl), —O(alkyl), C1-6 alkyl oralkyl-cycloalkyl with hydron replaced by hydroxyl group, a 3 to 7membered cycloalkyl or heterocycloalkyl, optionally containing a —(C═O)—group, or a 5 to 6 membered aryl or heteroaryl group, whichheterocycloalkyl or heteroaryl group can contain from one to threeheteroatoms independently selected from O, N or S, and the cycloalkyl,heterocycloalkyl, aryl or heteroaryl group can be unsubstituted orsubstituted with from one to three substituents independently selectedfrom halogen, C1-6 alkyl groups, hydroxylated C1-6 alkyl, C1-6 alkylcontaining thioether, ether, sulfone, sulfoxide, fluorine substitutedether or cyano group;R₁₇ is selected from the group consisting of (CH₂)nC(O)NR^(k)R^(l),wherein R^(k) and R^(l) are independently selected from H, C1-6 alkyl,hydrxylated C1-6 alkyl, C1-6 alkoxy alkyl, C1-6 alkyl with one ormultiple hydrogens replaced by fluorine, C1-6 alkyl with one carbonreplaced by S(O), S(O)(O), C1-6 alkoxyalkyl with one or multiplehydrogens replaced by fluorine, C1-6 alkyl with hydrogen replaced by acyano group, 5 and 6 membered aryl or heteroaryl, aklyl aryl with alkylgroup containing 1-6 carbons, and alkyl heteroaryl with alkyl groupcontaining 1-6 carbons, wherein the aryl or heteroaryl group can befurther substituted;R₁₈ is selected from the group consisting of substituted aryl,heteroaryl, alkyl, cycloalkyl, the substitution is preferably —N(C1-4alkyl)(cycloalkyl), —N(C1-4 alkyl)alkyl-cycloalkyl, and —N(C1-4alkyl)[(alkyl)-(heterocycle-substituted)-cycloalkyl];R₁₉ is selected from the group consisting of aryl, heteroaryl, bicyclicheteroaryl, and these aryl or hetroaryl groups can be substituted withhalogen, C1-6 alkyl, C1-6 cycloalkyl, CF₃, F, CN, alkyne, alkyl sulfone,the halogen substitution can be mon- bis- or tri-substituted;R₂₀ and R₂₁ are independently selected from C1-6 alkyl, C1-6 cycloalkyl,C1-6 alkoxy, hydoxylated C1-6 alkoxy, and fluorine substituted C1-6alkoxy, wherein R₂₀ and R₂₁ can further be connected to form a 5, 6 and7-membered cyclic or heterocyclic ring, which can further besubstituted;R₂₂ is selected from the group consisting of H, C1-6 alkyl, C1-6cycloalkyl, carboxylic acid, carboxylic acid ester, amide, reverseamide, sulfonamide, reverse sulfonamide, N-acyl urea,nitrogen-containing 5-membered heterocycle, the 5-membered heterocyclescan be further substituted with C1-6 alkyl, alkoxy, fluorine-substitutedalkyl, CN, and alkylsulfone;R₂₃ is selected from aryl, heteroaryl, —O-aryl, —O-heteroaryl, —O-alkyl,—O-alkyl-cycloalkyl, —NH— alkyl, —NH-alkyl-cycloalkyl, —N(H)-aryl,—N(H)-heteroaryl, —N(alkyl)-aryl, —N(alkyl)-heteroaryl, the aryl orheteroaryl groups can be substituted with halogen, C1-6 alkyl,hydoxylated C1-6 alkyl, cycloalkyl, fluorine-substituted C1-6 alkyl, CN,alkoxy, alkyl sulfone, amide and sulfonamide;R₂₄ is selected from the group consisting of —CH2-(C1-6 alkyl),—CH2-cycloalkyl, —CH2-aryl, CH2-heteroaryl, where alkyl, cycloalkyl,aryl and heteroaryl can be substituted with halogen, alkoxy, hydoxylatedalkyl, cyano-substituted alkyl, cycloalyl and substituted cycloalkyl;R₂₅ is selected from the group consisting of C1-6 alkyl, C1-6alkyl-cycloalkyl, alkoxy-substituted alkyl, hydroxylated alkyl, aryl,heteroaryl, substituted aryl or heteroaryl, 5,6, and 7-memberednitrogen-containing saturated heterocycles, 5,6-fused and 6,6-fusednitrogen-containing saturated heterocycles and these saturatedheterocycles can be substituted with C1-6 alkyl, fluorine-substitutedC1-6 alkyl, alkoxy, aryl and heteroaryl group;R₂₆ is selected from the group consisting of C1-6 alkyl, C3-6cycloalkyl, the alkyl or cycloalkyl can be substituted with —OH, alkoxy,fluorine-substituted alkoxy, fluorine-substituted alkyl, —NH₂,—NH-alkyl, NH—C(O)alkyl, —NH—S(O)₂-alkyl, and —S(O)₂-alkyl;R₂₇ is selected from the group consisting of aryl, heteroaryl, bicyclicheteroaryl, wherein the aryl or heteroaryl groups can be substitutedwith C1-6 alkyl, alkoxy, NH2, NH-alkyl, halogen, or —CN, and thesubstitution can be independently mono-, bis- and tri-substitution;R₂₈ is selected from the group consisting of aryl, 5 and 6-memberedheteroaryl, bicyclic heteroaryl, cycloalkyl, saturated heterocycle suchas piperidine, piperidinone, tetrahydropyran, N-acyl-piperidine, whereinthe cycloalkyl, saturated heterocycle, aryl or heteroaryl can be furthersubstituted with —OH, alkoxy, mono-, bis- or tri-substitution includinghalogen, —CN, alkyl sulfone, and fluorine substituted alkyl groups; andR_(1″) is selected from the group consisting of alkyl, aryl substitutedalkyl, alkoxy substituted alkyl, cycloalkyl, aryl-substitutedcycloalkyl, and alkoxy substituted cycloalkyl.

In certain embodiments, the heterocycles in R^(f) and R^(g) aresubstituted pyrrolidine, substituted piperidine, substituted piperizine.

Unless the context indicates otherwise, the following terms can mean:

The term “independently” is used herein to indicate that the variable,which is independently applied, varies independently from application toapplication.

The term “alkyl” shall mean within its context a linear, branch-chainedor cyclic fully saturated hydrocarbon radical or alkyl group, preferablya C₁-C₁₀, more preferably a C₁-C₆, alternatively a C₁-C₃ alkyl group,which may be optionally substituted. Examples of alkyl groups aremethyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl,n-decyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl,cyclobutyl, cyclopentyl, cyclopen-tylethyl, cyclohexylethyl andcyclohexyl, among others. In certain embodiments, the alkyl group isend-capped with a halogen group (Br, Cl, F, or I).

The term “lower alkyl” refers to methyl, ethyl or propyl

The term “lower alkoxy” refers to methoxy, ethoxy or propoxy.

The term “Alkenyl” refers to linear, branch-chained or cyclic C₂-C₁₀(preferably C₂-C₆) hydrocarbon radicals containing at least one C═Cbond.

The term “Alkynyl” refers to linear, branch-chained or cyclic C₂-C₁₀(preferably C₂-C₆) hydrocarbon radicals containing at least one C≡Cbond.

The term “alkylene” when used, refers to a —(CH₂)_(n)— group (n is aninteger generally from 0-6), which may be optionally substituted. Whensubstituted, the alkylene group preferably is substituted on one or moreof the methylene groups with a C₁-C₆ alkyl group (including acyclopropyl group or a t-butyl group), but may also be substituted withone or more halo groups, preferably from 1 to 3 halo groups or one ortwo hydroxyl groups, O—(C₁-C₆ alkyl) groups or amino acid sidechains asotherwise disclosed herein. In certain embodiments, an alkylene groupmay be substituted with a urethane or alkoxy group (or other group)which is further substituted with a polyethylene glycol chain (of from 1to 10, preferably 1 to 6, often 1 to 4 ethylene glycol units) to whichis substituted (preferably, but not exclusively on the distal end of thepolyethylene glycol chain) an alkyl chain substituted with a singlehalogen group, preferably a chlorine group. In still other embodiments,the alkylene (often, a methylene) group, may be substituted with anamino acid sidechain group such as a sidechain group of a natural orunnatural amino acid, for example, alanine, β-alanine, arginine,asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine,glycine, phenylalanine, histidine, isoleucine, lysine, leucine,methionine, proline, serine, threonine, valine, tryptophan or tyrosine.

The term “unsubstituted” shall mean substituted only with hydrogenatoms. A range of carbon atoms which includes C₀ means that carbon isabsent and is replaced with H. Thus, a range of carbon atoms which isC₀-C₆ includes carbons atoms of 1, 2, 3, 4, 5 and 6 and for C₀, H standsin place of carbon.

The term “substituted” or “optionally substituted” shall meanindependently (i.e., where more than substituent occurs, eachsubstituent is independent of another substituent) one or moresubstituents (independently up to five substituents, preferably up tothree substituents, often 1 or 2 substituents on a moiety in a compoundaccording to the present invention and may include substituents whichthemselves may be further substituted) at a carbon (or nitrogen)position anywhere on a molecule within context, and includes assubstituents hydroxyl, thiol, carboxyl, cyano (CN), nitro (NO₂), halogen(preferably, 1, 2 or 3 halogens, especially on an alkyl, especially amethyl group such as a trifluoromethyl), an alkyl group (preferably,C₁-C₁₀, more preferably, C₁-C₆), aryl (especially phenyl and substitutedphenyl for example benzyl or benzoyl), alkoxy group (preferably, C₁-C₆alkyl or aryl, including phenyl and substituted phenyl), thioether(C₁-C₆ alkyl or aryl), acyl (preferably, C₁-C₆ acyl), ester or thioester(preferably, C₁-C₆ alkyl or aryl) including alkylene ester (such thatattachment is on the alkylene group, rather than at the ester functionwhich is preferably substituted with a C₁-C₆ alkyl or aryl group),preferably, C₁-C₆ alkyl or aryl, halogen (preferably, F or Cl), amine(including a five- or six-membered cyclic alkylene amine, furtherincluding a C₁-C₆ alkyl amine or a C₁-C₆ dialkyl amine which alkylgroups may be substituted with one or two hydroxyl groups) or anoptionally substituted —N(C₀-C₆ alkyl)C(O)(O—C₁-C₆ alkyl) group (whichmay be optionally substituted with a polyethylene glycol chain to whichis further bound an alkyl group containing a single halogen, preferablychlorine substituent), hydrazine, amido, which is preferably substitutedwith one or two C₁-C₆ alkyl groups (including a carboxamide which isoptionally substituted with one or two C₁-C₆ alkyl groups), alkanol(preferably, C₁-C₆ alkyl or aryl), or alkanoic acid (preferably, C₁-C₆alkyl or aryl). Substituents according to the present invention mayinclude, for example —SiR₁R₂R₃ groups where each of R₁ and R₂ is asotherwise described herein and R₃ is H or a C₁-C₆ alkyl group,preferably R₁, R₂, R₃ in this context is a C₁-C₃ alkyl group (includingan isopropyl or t-butyl group). Each of the above-described groups maybe linked directly to the substituted moiety or alternatively, thesubstituent may be linked to the substituted moiety (preferably in thecase of an aryl or heteraryl moiety) through an optionally substituted—(CH₂)_(m)— or alternatively an optionally substituted —(OCH₂)_(m)—,—(OCH₂CH₂)_(m)— or —(CH₂CH₂O)_(m)— group, which may be substituted withany one or more of the above-described substituents. Alkylene groups—(CH₂)_(m)— or —(CH₂)_(m)— groups or other chains such as ethyleneglycol chains, as identified above, may be substituted anywhere on thechain. Preferred substituents on alkylene groups include halogen orC₁-C₆ (preferably C₁-C₃) alkyl groups, which may be optionallysubstituted with one or two hydroxyl groups, one or two ether groups(O—C₁-C₆ groups), up to three halo groups (preferably F), or a sidechain of an amino acid as otherwise described herein and optionallysubstituted amide (preferably carboxamide substituted as describedabove) or urethane groups (often with one or two C₀-C₆ alkylsubstituents, which group(s) may be further substituted). In certainembodiments, the alkylene group (often a single methylene group) issubstituted with one or two optionally substituted C₁-C₆ alkyl groups,preferably C₁-C₄ alkyl group, most often methyl or O-methyl groups or asidechain of an amino acid as otherwise described herein. In the presentinvention, a moiety in a molecule may be optionally substituted with upto five substituents, preferably up to three substituents. Most often,in the present invention moieties which are substituted are substitutedwith one or two substituents.

The term “substituted” (each substituent being independent of any othersubstituent) shall also mean within its context of use C₁-C₆ alkyl,C₁-C₆ alkoxy, halogen, amido, carboxamido, sulfone, includingsulfonamide, keto, carboxy, C₁-C₆ ester (oxyester or carbonylester),C₁-C₆ keto, urethane —O—C(O)—NR₁R₂ or —N(R₁)—C(O)—O—R₁, nitro, cyano andamine (especially including a C₁-C₆ alkylene-NR₁R₂, a mono- or di-C₁-C₆alkyl substituted amines which may be optionally substituted with one ortwo hydroxyl groups). Each of these groups contain unless otherwiseindicated, within

will include for example, —NH—, —NHC(O)—, —O—, ═O, —(CH₂)_(m)— (here, mand n are in context, 1, 2, 3, 4, 5 or 6), —S—, —S(O)—, SO₂— or—NH—C(O)—NH—, —(CH₂)OH, —(CH₂)—SH, —(CH₂)_(n)COOH, C₁-C₆ alkyl,—(CH₂)_(n)O—(C₁-C₆ alkyl), —(CH₂)_(n)C(O)—(C₁-C₆ alkyl),—(CH₂)_(n)OC(O)—(C₁-C₆ alkyl), —(CH₂)_(n)C(O)O—(C₁-C₆ alkyl),—(CH₂)_(n)NHC(O)—R₁, —(CH₂)_(n)C(O)—NR₁R₂, —(OCH₂)OH, —(CH₂O)_(n)COOH,C₁-C₆ alkyl, —(OCH₂)_(n)O—(C₁-C₆ alkyl), —(CH₂O)C(O)—(C₁-C₆ alkyl),—(OCH₂)_(n)NHC(O)—R₁, —(CH₂O)_(n)C(O)—NR₁R₂, —S(O)₂—R_(S), —S(O)—R_(S)(R_(S) is C₁-C₆ alkyl or a —(CH₂)_(m)—NR₁R₂ group), NO₂, CN or halogen(F, Cl, Br, I, preferably F or Cl), depending on the context of the useof the substituent. R₁ and R₂ are each, within context, H or a C₁-C₆alkyl group (which may be optionally substituted with one or twohydroxyl groups or up to three halogen groups, preferably fluorine). Theterm “substituted” shall also mean, within the chemical context of thecompound defined and substituent used, an optionally substituted aryl orheteroaryl group or an optionally substituted heterocyclic group asotherwise described herein. Alkylene groups may also be substituted asotherwise disclosed herein, preferably with optionally substituted C₁-C₆alkyl groups (methyl, ethyl or hydroxymethyl or hydroxyethyl ispreferred, thus providing a chiral center), a sidechain of an amino acidgroup as otherwise described herein, an amido group as describedhereinabove, or a urethane group O—C(O)—NR₁R₂ group where R₁ and R₂ areas otherwise described herein, although numerous other groups may alsobe used as substituents. Various optionally substituted moieties may besubstituted with 3 or more substituents, preferably no more than 3substituents and preferably with 1 or 2 substituents. It is noted thatin instances where, in a compound at a particular position of themolecule substitution is required (principally, because of valency), butno substitution is indicated, then that substituent is construed orunderstood to be H, unless the context of the substitution suggestsotherwise.

The term “aryl” or “aromatic”, in context, refers to a substituted (asotherwise described herein) or unsubstituted monovalent aromatic radicalhaving a single ring (e.g., benzene, phenyl, benzyl) or condensed rings(e.g., naphthyl, anthracenyl, phenanthrenyl, etc.) and can be bound tothe compound according to the present invention at any available stableposition on the ring(s) or as otherwise indicated in the chemicalstructure presented. Other examples of aryl groups, in context, mayinclude heterocyclic aromatic ring systems, “heteroaryl” groups havingone or more nitrogen, oxygen, or sulfur atoms in the ring (moncyclic)such as imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine,pyrimidine, pyrazine, triazole, oxazole or fused ring systems such asindole, quinoline, indoline, azaindoline, benzofuran, etc., amongothers, which may be optionally substituted as described above. Amongthe heteroaryl groups which may be mentioned include nitrogen-containingheteroaryl groups such as pyrrole, pyridine, pyridone, pyridazine,pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine,tetrazole, indole, isoindole, indoline, azaindoline, purine, indazole,quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline,dihydroisoquinoline, tetrahydroisoquinoline, quinolizine, phthalazine,naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine,imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine,phenanthridine, carbazole, carbazoline, pyrimidine, phenanthroline,phenacene, oxadiazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidineand pyridopyrimidine; sulfur-containing aromatic heterocycles such asthiophene and benzothiophene; oxygen-containing aromatic heterocyclessuch as furan, pyran, cyclopentapyran, benzofuran and isobenzofuran; andaromatic heterocycles comprising 2 or more hetero atoms selected fromamong nitrogen, sulfur and oxygen, such as thiazole, thiadizole,isothiazole, benzoxazole, benzothiazole, benzothiadiazole,phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole,imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine,furopyrimidine, thienopyrimidine and oxazole, among others, all of whichmay be optionally substituted.

The term “substituted aryl” refers to an aromatic carbocyclic groupcomprised of at least one aromatic ring or of multiple condensed ringsat least one of which being aromatic, wherein the ring(s) aresubstituted with one or more substituents. For example, an aryl groupcan comprise a substituent(s) selected from: —(CH₂)_(n)OH,—(CH₂)_(n)—O—(C₁-C₆)alkyl, —(CH₂)_(n)—O—(CH₂)_(n)—(C₁-C₆)alkyl,—(CH₂)_(n)—C(O)(C₀-C₆) alkyl, —(CH₂)_(n)—C(O)O(C₀-C₆)alkyl,—(CH₂)_(n)—OC(O)(C₀-C₆)alkyl, amine, mono- or di-(C₁-C₆ alkyl) aminewherein the alkyl group on the amine is optionally substituted with 1 or2 hydroxyl groups or up to three halo (preferably F, CO groups, OH,COOH, C₁-C₆ alkyl, preferably CH₃, CF₃, OMe, OCF₃, NO₂, or CN group(each of which may be substituted in ortho-, meta- and/or para-positionsof the phenyl ring, preferably para-), an optionally substituted phenylgroup (the phenyl group itself is preferably substituted with a linkergroup attached to a PTM group, including a ULM group), and/or at leastone of F, Cl, OH, COOH, CH₃, CF₃, OMe, OCF₃, NO₂, or CN group (inortho-, meta- and/or para-positions of the phenyl ring, preferablypara-), a naphthyl group, which may be optionally substituted, anoptionally substituted heteroaryl, preferably an optionally substitutedisoxazole including a methylsubstituted isoxazole, an optionallysubstituted oxazole including a methylsubstituted oxazole, an optionallysubstituted thiazole including a methyl substituted thiazole, anoptionally substituted isothiazole including a methyl substitutedisothiazole, an optionally substituted pyrrole including amethylsubstituted pyrrole, an optionally substituted imidazole includinga methylimidazole, an optionally substituted benzimidazole ormethoxybenzylimidazole, an optionally substituted oximidazole ormethyloximidazole, an optionally substituted diazole group, including amethyldiazole group, an optionally substituted triazole group, includinga methylsubstituted triazole group, an optionally substituted pyridinegroup, including a halo-(preferably, F) or methylsubstitutedpyridinegroup or an oxapyridine group (where the pyridine group is linked to thephenyl group by an oxygen), an optionally substituted furan, anoptionally substituted benzofuran, an optionally substituteddihydrobenzofuran, an optionally substituted indole, indolizine orazaindolizine (2, 3, or 4-azaindolizine), an optionally substitutedquinoline, and combinations thereof.

“Carboxyl” denotes the group —C(O)OR, where R is hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl, whereas these generic substituents have meanings which areidentical with definitions of the corresponding groups defined herein.

The term “heteroaryl” or “hetaryl” can mean but is in no way limited toan optionally substituted quinoline (which may be attached to thepharmacophore or substituted on any carbon atom within the quinolinering), an optionally substituted indole (including dihydroindole), anoptionally substituted indolizine, an optionally substitutedazaindolizine (2, 3 or 4-azaindolizine) an optionally substitutedbenzimidazole, benzodiazole, benzoxofuran, an optionally substitutedimidazole, an optionally substituted isoxazole, an optionallysubstituted oxazole (preferably methyl substituted), an optionallysubstituted diazole, an optionally substituted triazole, a tetrazole, anoptionally substituted benzofuran, an optionally substituted thiophene,an optionally substituted thiazole (preferably methyl and/or thiolsubstituted), an optionally substituted isothiazole, an optionallysubstituted triazole (preferably a 1,2,3-triazole substituted with amethyl group, a triisopropylsilyl group, an optionally substituted—(CH₂)_(m)—O—C₁-C₆ alkyl group or an optionally substituted—(CH₂)_(m)—C(O)—O—C₁-C₆ alkyl group), an optionally substituted pyridine(2-, 3, or 4-pyridine) or a group according to the chemical structure.

wherein

-   S^(c) is CHR^(SS), NR^(URE), or O;-   R^(HET) is H, CN, NO₂, halo (preferably Cl or F), optionally    substituted C₁-C₆ alkyl (preferably substituted with one or two    hydroxyl groups or up to three halo groups (e.g. CF₃), optionally    substituted O(C₁-C₆ alkyl) (preferably substituted with one or two    hydroxyl groups or up to three halo groups) or an optionally    substituted acetylenic group —C≡C—R_(a) where R_(a) is H or a C₁-C₆    alkyl group (preferably C₁-C₃ alkyl);-   R^(SS) is H, CN, NO₂, halo (preferably F or Cl), optionally    substituted C₁-C₆ alkyl (preferably substituted with one or two    hydroxyl groups or up to three halo groups), optionally substituted    O—(C₁-C₆ alkyl) (preferably substituted with one or two hydroxyl    groups or up to three halo groups) or an optionally substituted    —C(O)(C₁-C₆ alkyl) (preferably substituted with one or two hydroxyl    groups or up to three halo groups);-   R^(URE) is H, a C₁-C₆ alkyl (preferably H or C₁-C₃ alkyl) or a    —C(O)(C₁-C₆ alkyl), each of which groups is optionally substituted    with one or two hydroxyl groups or up to three halogen, preferably    fluorine groups, or an optionally substituted heterocycle, for    example piperidine, morpholine, pyrrolidine, tetrahydrofuran,    tetrahydrothiophene, piperidine, piperazine, each of which is    optionally substituted, and-   Y^(C) is N or C—R^(YC), where R^(YC) is H, OH, CN, NO₂, halo    (preferably Cl or F), optionally substituted C₁-C₆ alkyl (preferably    substituted with one or two hydroxyl groups or up to three halo    groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl) (preferably    substituted with one or two hydroxyl groups or up to three halo    groups) or an optionally substituted acetylenic group —C≡C—R_(a)    where R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl).

The term “Heterocycle” refers to a cyclic group which contains at leastone heteroatom, e.g., N, O or S, and may be aromatic (heteroaryl) ornon-aromatic. Thus, the heteroaryl moieties are subsumed under thedefinition of heterocycle, depending on the context of its use.Exemplary heteroaryl groups are described hereinabove.

Exemplary heterocyclics include: azetidinyl, benzimidazolyl,1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl,benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl,dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane,1,4-dioxane, furyl, homopiperidinyl, imidazolyl, imidazolinyl,imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl,isothiazolyl, isoxazolidinyl isoxazolyl, morpholinyl, naphthyridinyl,oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl,N-methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl,pyrazolinyl, pyridyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline,thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene, oxane, oxetanyl,oxathiolanyl, thiane among others.

Heterocyclic groups can be optionally substituted with a member selectedfrom the group consisting of alkoxy, substituted alkoxy, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxy,carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol,thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-substituted alkyl, —SOaryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl, oxo (═O), and—SO₂-heteroaryl. Such heterocyclic groups can have a single ring ormultiple condensed rings. Examples of nitrogen heterocycles andheteroaryls include, but are not limited to, pyrrole, imidazole,pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine,isoindole, indole, indazole, purine, quinolizine, isoquinoline,quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline,cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine,phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine,phenothiazine, imidazolidine, imidazoline, piperidine, piperazine,indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like aswell as N-alkoxy-nitrogen containing heterocycles. The term“heterocyclic” also includes bicyclic groups in which any of theheterocyclic rings is fused to a benzene ring or a cyclohexane ring oranother heterocyclic ring (for example, indolyl, quinolyl, isoquinolyl,tetrahydroquinolyl, and the like).

The term “cycloalkyl” can mean but is in no way limited to univalentgroups derived from monocyclic or polycyclic alkyl groups orcycloalkanes, as defined herein, e.g., saturated monocyclic hydrocarbongroups having from three to twenty carbon atoms in the ring, including,but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and the like. The term “substituted cycloalkyl” can mean butis in no way limited to a monocyclic or polycyclic alkyl group and beingsubstituted by one or more substituents, for example, amino, halogen,alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro,mercapto or sulfo, whereas these generic substituent groups havemeanings which are identical with definitions of the correspondinggroups as defined in this legend.

“Heterocycloalkyl” refers to a monocyclic or polycyclic alkyl group inwhich at least one ring carbon atom of its cyclic structure beingreplaced with a heteroatom selected from the group consisting of N, O, Sor P. “Substituted heterocycloalkyl” refers to a monocyclic orpolycyclic alkyl group in which at least one ring carbon atom of itscyclic structure being replaced with a heteroatom selected from thegroup consisting of N, O, S or P and the group is containing one or moresubstituents selected from the group consisting of halogen, alkyl,substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto orsulfo, whereas these generic substituent group have meanings which areidentical with definitions of the corresponding groups as defined inthis legend.

More specifically, non-limiting examples of MLMs include those shownbelow as well as those ‘hybrid’ molecules that arise from thecombination of 1 or more of the different features shown in themolecules below.

Using MBM or MLM in Formula A-1 through A-8, the following PROTACs canbe prepared to target a particular protein for degradation, where ‘L” isa connector (i.e. a linker group), and “PTM” is a ligand binding to atarget protein.

In certain embodiments, the description provides a bifunctional moleculecomprising a structure selected from the group consisting of:

whereinX, R^(a), Y, Z, A, A′, A″, R₁, R₂, R₃, R₄, R₅, R₆, R^(b), R^(c), R^(d),R₇, R^(e), R^(f), R^(g), R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇,R^(k), R^(l), R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, andR_(1″) are as defined herein.

In certain embodiments, the description provides bifunctional orchimeric molecules with the structure: PTM-L-MLM, wherein PTM is aprotein target binding moiety coupled to an MLM by L, wherein L is abond (i.e., absent) or a chemical linker. In certain embodiments, theMLM has a structure selected from the group consisting of A-1-1, A-1-2,A-1-3, and A-1-4:

wherein R1′ and R2′ are independently selected from the group consistingof F, Cl, Br, I, acetylene, CN, CF₃ and NO₂;R3′ is selected from the group consisting of —OCH₃, —OCH₂CH₃, —OCH₂CH₂F,—OCH₂CH₂OCH₃, and —OCH(CH₃)₂;R4′ is selected from the group consisting of H, halogen, —CH₃, —CF₃,—OCH₃, —C(CH₃)₃, —CH(CH₃)₂, -cyclopropyl, —CN, —C(CH₃)₂OH,—C(CH₃)₂OCH₂CH₃, —C(CH₃)₂CH₂OH, —C(CH₃)₂CH₂OCH₂CH₃,—C(CH₃)₂CH₂OCH₂CH₂OH, —C(CH₃)₂CH₂OCH₂CH₃, —C(CH₃)₂CN, —C(CH₃)₂C(O)CH₃,—C(CH₃)₂C(O)NHCH₃, —C(CH₃)₂C(O)N(CH₃)₂, —SCH₃, —SCH₂CH₃, —S(O)₂CH₃,—S(O₂)CH₂CH₃, —NHC(CH₃)₃, —N(CH₃)₂, pyrrolidinyl, and 4-morpholinyl;R5′ is selected from the group consisting of halogen, -cyclopropyl,—S(O)₂CH₃, —S(O)₂CH₂CH₃, 1-pyrrolidinyl, —NH₂, —N(CH₃)₂, and —NHC(CH₃)₃;andR6′ is selected from the structures presented below where the linkerconnection point is indicated as “*”.Beside R6′ as the point for linker attachment, R4′ can also serve as thelinker attachment position. In the case that R4′ is the linkerconnection site, linker will be connected to the terminal atom of R4′groups shown above.

In certain embodiments, the linker connection position is at least oneof R4′ or R6′ or both.

In certain embodiments, R6′ is independently selected from the groupconsisting of H,

wherein “*” indicates the point of attachment of the linker.

In certain embodiments, the linker is attached to at least one of R1′,R2′, R3′, R4′, R5′, R6′, or a combination thereof.

In certain embodiments, the description provides bifunctional orchimeric molecules with the structure: PTM-L-MLM, wherein PTM is aprotein target binding moiety coupled to an MLM by L, wherein L is abond (i.e., absent) or a chemical linker. In certain embodiments, theMLM has a structure selected from the group consisting of A-4-1, A-4-2,A-4-3, A-4-4, A-4-5, and A-4-6:

wherein:R7′ is a member selected from the group consisting of halogen, mono-,and di- or tri-substituted halogen;R8′ is selected from the group consisting of H, —F, —Cl, —Br, —I, —CN,—NO₂, ethylnyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl, methoxy,ethoxy, isopropoxy, —OH, other C1-6 alkyl, other C1-6 alkenyl, and C1-6alkynyl, mono-, di- or tri-substituted;R9′ is selected from the group consistin of alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,substituted aryl, hetero aryl, substituted heteroaryl, cycloalkyl,substituted cycloalkyl, alkenyl, and substituted cycloalkenyl;Z is selected from the group consistin of H, —OCH₃, —OCH₂CH₃, andhalogen;R10′ and R11′ are each independently selected from the group consistingof H, (CH₂)_(n)—R′, (CH₂)_(n)—NR′R″, (CH₂)_(n)—NR′COR″,(CH₂)_(n)—NR′SO₂R″, (CH₂)_(n)—COOH, (CH₂)_(n)—COOR′, (CH)_(n)—CONR′R″,(CH₂)_(n)—OR′, (CH₂)_(n)—SR′, (CH₂)_(n)—SOR′, (CH₂)_(n)—CH(OH)—R′,(CH₂)_(n)—COR′, (CH₂)_(n)—SO₂R % (CH₂)_(n)—SONR′R″, (CH₂)_(n)—SO₂NR′R″,(CH₂CH₂O)_(m)—(CH₂)_(n)—R′, (CH₂CH₂O)_(m)—(CH₂)_(n)—OH,(CH₂CH₂O)_(m)—(CH₂)_(n)—OR′, (CH₂CH₂O)_(m)—(CH₂)_(n)—NR′R″,(CH₂CH₂O)_(m)—(CH₂)_(n)—NR′COR″, (CH₂CH₂O)_(m)(CH₂)_(n)—NR′SO₂R″,(CH₂CH₂O)_(in)(CH₂)_(n)—COOH, (CH₂CH₂O)_(in)(CH₂)_(n)—COOR′,(CH₂CH₂O)_(m)—(CH2)_(n)—CONR′R″, (CH₂CH₂O)_(m)—(CH₂)_(n)—SO₂R′,(CH₂CH₂O)_(m)—(CH₂)_(n)—COR′, (CH₂CH₂O)_(m)—(CH₂)_(n)—SONR′R″,(CH₂CH₂O)_(m)—(CH₂), —SO₂NR′R″, (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)R′,(CH₂)p-(CH₂CH₂O)_(m)—(CH₂)_(n)—OH, (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)n-OR′,(CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—NR′R″,(CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—NR′COR″, (CH₂)_(p)—(CH₂CH₂O)m-(CH₂)_(n)—NR′SO₂R″, (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—COOH,(CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—COOR′,(CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—CONR′R″,(CH₂)p-(CH₂CH₂O)_(m)—(CH₂)_(n)—SO₂R′,(CH2)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—COR′,(CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—SONR′R″,(CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—SO₂NR′R″, Aryl-(CH₂)_(n)—COOH, andheteroaryl-alkyl-CO-alkyl-NR′R″m, wherein the alkyl may be substitutedwith OR′, and heteroaryl-(CH₂)_(n)-heterocycle wherein the heterocyclemay optionally be substituted with alkyl, hydroxyl, COOR′ and COR′;wherein R′ and R″ are selected from H, alkyl, alkyl substituted withhalogen, hydroxyl, NH2, NH(alkyl), N(alkyl)₂, oxo, carboxy, clcloalkyland heteroaryl;m, n, and p are independently 0 to 6;R12′ is selected from the group consisting of —O-(alkyl),—O-(alkyl)-akoxy, —C(O)-(alkyl), —C(OH)-alkyl-alkoxy, —C(O)—NH-(alkyl),—C(O)—N-(alkyl)₂, —S(O)-(alkyl), S(O)₂-(alkyl), —C(O)-(cyclic amine),and —O-aryl-(alkyl), —O-aryl-(alkoxy);R1″ is selected from the group consisting of alkyl, aryl substitutedalkyl, aloxy substituted alkyl, cycloalkyl, ary-substituted cycloalkyl,and alkoxy substituted cycloalkyl.

In any of the aspects or embodiments described herein, the alkyl, alkoxyor the like can be a lower alkyl or lower alkoxy.

In certain embodiments, the linker connection position is at least oneof Z, R8′, R9′, R10′, R11″, R12″, or R1″.

The method used to design chimeric molecules as presented in A-1-1through A-1-4, A-4-1 through A-4-6 can be applied to MBM or MLM withformula A-2, A-3, A-5, A-6, A-7 and A-8, wherein the solvent exposedarea in the MBM or MLM can be connected to linker “L” which will beattached to target protein ligand “PTM”, to construct PROTACs.

Exemplary Linkers

In certain embodiments, the compounds as described herein can bechemically linked or coupled via a chemical linker (L). In certainembodiments, the linker group L is a group comprising one or morecovalently connected structural units of B (e.g., —B₁ . . . B_(q)—),wherein B₁ is a group coupled to at least one of a MBM, a PTM, or acombination thereof. In certain embodiments, B₁ links an MBM, a PTM, ora combination thereof. In certain embodiments B₁ links an MBM, a PTM ora combination thereof directly to another MBM, PTM, or combinationthereof. In other embodiments, B₁ links a MBM, a PTM, or a combinationthereof indirectly to another MBM, PTM, or combination thereof throughB_(q).

In certain embodiments, B₁ to B_(q) are, each independently, a bond,CR^(L1)R^(L2), O, S, SO, SO₂, NR^(L3), SO₂NR^(L3), SONR^(L3), CONR^(L3),NR^(L3)CONR^(L4), NR^(L3)SO₂NR^(L4), CO, CR^(L1)═CR^(L2), C≡C,SiR^(L1)R^(L2), P(O)R^(L1), P(O)OR^(L1), NR^(L3)C(═NCN)NR^(L4),NR^(L3)C(═NCN), NR^(L3)C(═CNO₂)NR^(L4), C₃₋₁₁cycloalkyl optionallysubstituted with 0-6 R^(L1) and/or R^(L2) groups, C₃₋₁₁heteocyclyloptionally substituted with 0-6 R^(L1) and/or R^(L2) groups, aryloptionally substituted with 0-6 R^(L1) and/or R^(L2) groups, heteroaryloptionally substituted with 0-6 R^(L1) and/or R^(L2) groups, whereR^(L1) or R^(L2), each independently, can be linked to other B groups toform cycloalkyl and/or heterocyclyl moeity which can be furthersubstituted with 0-4 R¹⁻⁵ groups; wherein

-   R^(L1), R^(L2), R^(L3), R^(L4) and R^(L5) are, each independently,    H, halo, C₁₋₈alkyl, OC₁₋₈alkyl, SC₁₋₈alkyl, NHC₁₋₈alkyl,    N(C₁₋₈alkyl)₂, C₃₋₁₁cycloalkyl, aryl, heteroaryl, C₃₋₁₁heterocyclyl,    OC₁₋₈cycloalkyl, SC₁₋₈cycloalkyl, NHC₁₋₈cycloalkyl,    N(C₁₋₈cycloalkyl)₂, N(C₁₋₈cycloalkyl)(C₁₋₈alkyl), OH, NH₂, SH,    SO₂C₁₋₈alkyl, P(O)(OC₁₋₈alkyl)(C₁₋₈alkyl), P(O)(OC₁₋₈alkyl)₂,    CC—C₁₋₈ alkyl, CCH, CH═CH(C₁₋₈alkyl), C(C₁₋₈alkyl)═CH(C₁₋₈alkyl),    C(C₁₋₈alkyl)═C(C₁₋₈alkyl)₂, Si(OH)₃, Si(C₁₋₈alkyl)₃,    Si(OH)(C₁₋₈alkyl)₂, COC₁₋₈alkyl, CO₂H, halogen, CN, CF₃, CHF₂, CH₂F,    NO₂, SF₅, SO₂NHC₁₋₈alkyl, SO₂N(C₁₋₈alkyl)₂, SONHC₁₋₈alkyl,    SON(C₁₋₈alkyl)₂, CONHC₁₋₈alkyl, CON(C₁₋₈alkyl)₂,    N(C₁₋₈alkyl)CONH(C₁₋₈alkyl), N(C₁₋₈alkyl)CON(C₁-8alkyl)₂,    NHCONH(C₁₋₈alkyl), NHCON(C₁₋₈alkyl)₂, NHCONH₂,    N(C₁₋₈alkyl)SO₂NH(C₁₋₈alkyl), N(C₁₋₈alkyl) SO₂N(C₁₋₈alkyl)₂, NH    SO₂NH(C₁₋₈alkyl), NH SO₂N(C₁₋₈alkyl)₂, NH SO₂NH₂.

In certain embodiments, q is an integer greater than or equal to 0. Incertain embodiments, q is an integer greater than or equal to 1.

In certain embodiments, e.g., where q is greater than 2, B_(q) is agroup which is connected to MBM, and B₁ and B_(q) are connected viastructural units of B (number of such structural units of B: q-2).

In certain embodiments, e.g., where q is 2, B_(q) is a group which isconnected to B₁ and to a MBM.

In certain embodiments, e.g., where q is 1, the structure of the linkergroup L is —B₁—, and B₁ is a group which is connected to a MBM moietyand a PTM moiety.

In additional embodiments, q is an integer from 1 to 100, 1 to 90, 1 to80, 1 to 70, 1 to 60, 1 to 50, 1 to 40, 1 to 30, 1 to 20, or 1 to 10.

In certain embodiments, the linker (L) is selected from the groupconsisting of:

—(CH₂)_(n)-(lower alkyl)-, —(CH₂)_(n)-(lower alkoxyl)-,—(CH₂)_(n)-(lower alkoxyl)-OCH₂—C(O)—, —(CH₂)_(n)-(lower alkoxyl)-(loweralkyl)-OCH₂—C(O)—, —(CH₂)_(n)-(cycloalkyl)-(lower alkyl)-OCH₂—C(O)—,—(CH₂)_(n)-(hetero cycloalkyl)-, —(CH₂CH₂O)_(n)-(loweralkyl)-O—CH₂—C(O)—, —(CH₂CH₂O)_(n)-(hetero cycloalkyl)-O—CH₂—C(O)—,—(CH₂CH₂O)_(n)-Aryl-O—CH₂—C(O)—, —(CH₂CH₂O)_(n)-(heteroaryl)-O—CH₂—C(O)—, —(CH₂CH₂O)_(n)-(cyclo alkyl)-O-(heteroaryl)-O—CH₂—C(O)—, —(CH₂CH₂O)_(n)-(cyclo alkyl)-O-Aryl-O—CH₂—C(O)—,—(CH₂CH₂O)_(n)-(lower alkyl)-NH-Aryl-0-CH₂—C(O)—, —(CH₂CH₂O)_(n)-(loweralkyl)-O-Aryl-C(O)—, —(CH₂CH₂O)_(n)-cycloalkyl-O-Aryl-C(O)—,—(CH₂CH₂O)_(n)-cycloalkyl-O-(hetero aryl)1-C(O)—, where n can be 0 to 10

In additional embodiments, the linker group is optionally substituted(poly)ethyleneglycol having between 1 and about 100 ethylene glycolunits, between about 1 and about 50 ethylene glycol units, between 1 andabout 25 ethylene glycol units, between about 1 and 10 ethylene glycolunits, between 1 and about 8 ethylene glycol units and 1 and 6 ethyleneglycol units, between 2 and 4 ethylene glycol units, or optionallysubstituted alkyl groups interdispersed with optionally substituted, O,N, S, P or Si atoms. In certain embodiments, the linker is substitutedwith an aryl, phenyl, benzyl, alkyl, alkylene, or heterocycle group. Incertain embodiments, the linker may be asymmetric or symmetrical.

In any of the embodiments of the compounds described herein, the linkergroup may be any suitable moiety as described herein. In one embodiment,the linker is a substituted or unsubstituted polyethylene glycol groupranging in size from about 1 to about 12 ethylene glycol units, between1 and about 10 ethylene glycol units, about 2 about 6 ethylene glycolunits, between about 2 and 5 ethylene glycol units, between about 2 and4 ethylene glycol units.

Although the MLM (or ULM) group and PTM group may be covalently linkedto the linker group through any group which is appropriate and stable tothe chemistry of the linker, in preferred aspects of the presentinvention, the linker is independently covalently bonded to the MLMgroup and the PTM group preferably through an amide, ester, thioester,keto group, carbamate (urethane), carbon or ether, each of which groupsmay be inserted anywhere on the MLM group and PTM group to providemaximum binding of the MLM group on the ubiquitin ligase and the PTMgroup on the target protein to be degraded. (It is noted that in certainaspects where the PTM group is a ULM group, the target protein fordegradation may be the ubiquitin ligase itself). In certain preferredaspects, the linker may be linked to an optionally substituted alkyl,alkylene, alkene or alkyne group, an aryl group or a heterocyclic groupon the MLM and/or PTM groups.

In certain embodiments, “L” can be linear chains with linear atoms from4 to 24, the carbon atom in the linear chain can be substituted withoxygen, nitrogen, amide, fluorinated carbon, etc., such as thefollowing:

In certain embodiments, “L” can be nonlinear chains, and can bealiphatic or aromatic or heteroaromatic cyclic moieties, some examplesof “L” include but not be limited to the following:

wherein:

-   -   “X” in above structures can be linear chain with atoms ranging        from 2 to 14, and the mentioned chain can contain heteroatoms        such as oxygen; and    -   “Y” in above structures can be O, N, S(O)_(n) (n=0, 1, 2).

Exemplary PTMs

In preferred aspects of the invention, the PTM group is a group, whichbinds to target proteins. Targets of the PTM group are numerous in kindand are selected from proteins that are expressed in a cell such that atleast a portion of the sequences is found in the cell and may bind to aPTM group. The term “protein” includes oligopeptides and polypeptidesequences of sufficient length that they can bind to a PTM groupaccording to the present invention. Any protein in a eukaryotic systemor a microbial system, including a virus, bacteria or fungus, asotherwise described herein, are targets for ubiquitination mediated bythe compounds according to the present invention. Preferably, the targetprotein is a eukaryotic protein. In certain aspects, the protein bindingmoiety is a haloalkane (preferably a C₁-C₁₀ alkyl group which issubstituted with at least one halo group, preferably a halo group at thedistal end of the alkyl group (i.e., away from the linker or CLM group),which may covalently bind to a dehalogenase enzyme in a patient orsubject or in a diagnostic assay.

PTM groups according to the present invention include, for example,include any moiety which binds to a protein specifically (binds to atarget protein) and includes the following non-limiting examples ofsmall molecule target protein moieties: Hsp90 inhibitors, kinaseinhibitors, compounds targeting Human BET Bromodomain-containingproteins, HDAC inhibitors, human lysine methyltransferase inhibitors,angiogenesis inhibitors, nuclear hormone receptor compounds,immunosuppressive compounds, and compounds targeting the arylhydrocarbon receptor (AHR), among numerous others. The compositionsdescribed below exemplify some of the members of these nine types ofsmall molecule target protein binding moieties. Such small moleculetarget protein binding moieties also include pharmaceutically acceptablesalts, enantiomers, solvates and polymorphs of these compositions, aswell as other small molecules that may target a protein of interest.These binding moieties are linked to the ubiquitin ligase binding moietypreferably through a linker in order to present a target protein (towhich the protein target moiety is bound) in proximity to the ubiquitinligase for ubiquitination and degradation.

Any protein, which can bind to a protein target moiety or PTM group andacted on or degraded by an ubiquitin ligase is a target proteinaccording to the present invention. In general, target proteins mayinclude, for example, structural proteins, receptors, enzymes, cellsurface proteins, proteins pertinent to the integrated function of acell, including proteins involved in catalytic activity, aromataseactivity, motor activity, helicase activity, metabolic processes(anabolism and catrabolism), antioxidant activity, proteolysis,biosynthesis, proteins with kinase activity, oxidoreductase activity,transferase activity, hydrolase activity, lyase activity, isomeraseactivity, ligase activity, enzyme regulator activity, signal transduceractivity, structural molecule activity, binding activity (protein, lipidcarbohydrate), receptor activity, cell motility, membrane fusion, cellcommunication, regulation of biological processes, development, celldifferentiation, response to stimulus, behavioral proteins, celladhesion proteins, proteins involved in cell death, proteins involved intransport (including protein transporter activity, nuclear transport,ion transporter activity, channel transporter activity, carrieractivity, permease activity, secretion activity, electron transporteractivity, pathogenesis, chaperone regulator activity, nucleic acidbinding activity, transcription regulator activity, extracellularorganization and biogenesis activity, translation regulator activity.Proteins of interest can include proteins from eurkaryotes andprokaryotes including humans as targets for drug therapy, other animals,including domesticated animals, microbials for the determination oftargets for antibiotics and other antimicrobials and plants, and evenviruses, among numerous others.

In still other embodiments, the PTM group is a haloalkyl group, whereinsaid alkyl group generally ranges in size from about 1 or 2 carbons toabout 12 carbons in length, often about 2 to 10 carbons in length, oftenabout 3 carbons to about 8 carbons in length, more often about 4 carbonsto about 6 carbons in length. The haloalkyl groups are generally linearalkyl groups (although branched-chain alkyl groups may also be used) andare end-capped with at least one halogen group, preferably a singlehalogen group, often a single chloride group. Haloalkyl PT, groups foruse in the present invention are preferably represented by the chemicalstructure —(CH₂)_(v)-Halo where v is any integer from 2 to about 12,often about 3 to about 8, more often about 4 to about 6. Halo may be anyhalogen, but is preferably Cl or Br, more often Cl.

In another embodiment, the present invention provides a library ofcompounds. The library comprises more than one compound wherein eachcomposition has a formula of A-B, wherein A is a ubiquitin pathwayprotein binding moiety (preferably, an E3 ubiquitin ligase moiety asotherwise disclosed herein) and B is a protein binding member of amolecular library, wherein A is coupled (preferably, through a linkermoiety) to B, and wherein the ubiquitin pathway protein binding moietyrecognizes an ubiquitin pathway protein, in particular, an E3 ubiquitinligase, such as cereblon. In a particular embodiment, the librarycontains a specific cereblon E3 ubiquitin ligase binding moiety bound torandom target protein binding elements (e.g., a chemical compoundlibrary). As such, the target protein is not determined in advance andthe method can be used to determine the activity of a putative proteinbinding element and its pharmacological value as a target upondegradation by ubiquitin ligase.

The present invention may be used to treat a number of disease statesand/or conditions, including any disease state and/or condition in whichproteins are dysregulated and where a patient would benefit from thedegradation of proteins.

In an additional aspect, the description provides therapeuticcompositions comprising an effective amount of a compound as describedherein or salt form thereof, and a pharmaceutically acceptable carrier,additive or excipient, and optionally an additional bioactive agent. Thetherapeutic compositions modulate protein degradation in a patient orsubject, for example, an animal such as a human, and can be used fortreating or ameliorating disease states or conditions which aremodulated through the degraded protein. In certain embodiments, thetherapeutic compositions as described herein may be used to effectuatethe degradation of proteins of interest for the treatment oramelioration of a disease, e.g., cancer. In certain additionalembodiments, the disease is multiple myeloma.

In alternative aspects, the present invention relates to a method fortreating a disease state or ameliorating the symptoms of a disease orcondition in a subject in need thereof by degrading a protein orpolypeptide through which a disease state or condition is modulatedcomprising administering to said patient or subject an effective amount,e.g., a therapeutically effective amount, of at least one compound asdescribed hereinabove, optionally in combination with a pharmaceuticallyacceptable carrier, additive or excipient, and optionally an additionalbioactive agent, wherein the composition is effective for treating orameliorating the disease or disorder or symptom thereof in the subject.The method according to the present invention may be used to treat alarge number of disease states or conditions including cancer, by virtueof the administration of effective amounts of at least one compounddescribed herein. The disease state or condition may be a disease causedby a microbial agent or other exogenous agent such as a virus, bacteria,fungus, protozoa or other microbe or may be a disease state, which iscaused by overexpression of a protein, which leads to a disease stateand/or condition.

In another aspect, the description provides methods for identifying theeffects of the degradation of proteins of interest in a biologicalsystem using compounds according to the present invention.

The term “target protein” is used to describe a protein or polypeptide,which is a target for binding to a compound according to the presentinvention and degradation by ubiquitin ligase hereunder. Such smallmolecule target protein binding moieties also include pharmaceuticallyacceptable salts, enantiomers, solvates and polymorphs of thesecompositions, as well as other small molecules that may target a proteinof interest. These binding moieties are linked to CLM or ULM groupsthrough linker groups L.

Target proteins which may be bound to the protein target moiety anddegraded by the ligase to which the ubiquitin ligase binding moiety isbound include any protein or peptide, including fragments thereof,analogues thereof, and/or homologues thereof. Target proteins includeproteins and peptides having any biological function or activityincluding structural, regulatory, hormonal, enzymatic, genetic,immunological, contractile, storage, transportation, and signaltransduction. In certain embodiments, the target proteins includestructural proteins, receptors, enzymes, cell surface proteins, proteinspertinent to the integrated function of a cell, including proteinsinvolved in catalytic activity, aromatase activity, motor activity,helicase activity, metabolic processes (anabolism and catrabolism),antioxidant activity, proteolysis, biosynthesis, proteins with kinaseactivity, oxidoreductase activity, transferase activity, hydrolaseactivity, lyase activity, isomerase activity, ligase activity, enzymeregulator activity, signal transducer activity, structural moleculeactivity, binding activity (protein, lipid carbohydrate), receptoractivity, cell motility, membrane fusion, cell communication, regulationof biological processes, development, cell differentiation, response tostimulus, behavioral proteins, cell adhesion proteins, proteins involvedin cell death, proteins involved in transport (including proteintransporter activity, nuclear transport, ion transporter activity,channel transporter activity, carrier activity, permease activity,secretion activity, electron transporter activity, pathogenesis,chaperone regulator activity, nucleic acid binding activity,transcription regulator activity, extracellular organization andbiogenesis activity, translation regulator activity. Proteins ofinterest can include proteins from eurkaryotes and prokaryotes,including microbes, viruses, fungi and parasites, including humans,microbes, viruses, fungi and parasites, among numerous others, astargets for drug therapy, other animals, including domesticated animals,microbials for the determination of targets for antibiotics and otherantimicrobials and plants, and even viruses, among numerous others.

The term “protein target moiety” or PTM is used to describe a smallmolecule which binds to a target protein or other protein or polypeptideof interest and places/presents that protein or polypeptide in proximityto an ubiquitin ligase such that degradation of the protein orpolypeptide by ubiquitin ligase may occur. Non-limiting examples ofsmall molecule target protein binding moieties include Hsp90 inhibitors,kinase inhibitors, MDM2 inhibitors, compounds targeting Human BETBromodomain-containing proteins, HDAC inhibitors, human lysinemethyltransferase inhibitors, angiogenesis inhibitors, immunosuppressivecompounds, and compounds targeting the aryl hydrocarbon receptor (AHR),among numerous others. The compositions described below exemplify someof the members of these nine types of small molecule target protein.

Exemplary protein target moieties according to the present disclosureinclude, haloalkane halogenase inhibitors, Hsp90 inhibitors, kinaseinhibitors, MDM2 inhibitors, compounds targeting Human BETBromodomain-containing proteins, HDAC inhibitors, human lysinemethyltransferase inhibitors, angiogenesis inhibitors, immunosuppressivecompounds, and compounds targeting the aryl hydrocarbon receptor (AHR).

Additional exemplary protein targets to which a PTM may bind and may beincorporated into compounds as described herein include, Adrenomedullin(AM), Angiopoietin (Ang), Autocrine motility factor, Bone morphogeneticproteins (BMPs), Ciliary neurotrophic factor family Ciliary neurotrophicfactor (CNTF), Leukemia inhibitory factor (LIF), Interleukin-(IL-6),Colony-stimulating factors Macrophage colony-stimulating factor (m-CSF),Granulocyte colony-stimulating factor (G-CSF), Granulocyte macrophagecolony-stimulating factor (GM-CSF), Epidermal growth factor (EGF),Ephrins Ephrin A1, Ephrin A2, Ephrin A3, Ephrin A4, Ephrin A5, EphrinB1, Ephrin B2, Ephrin B3, Erythropoietin (EPO), Fibroblast growth factor(FGF), Foetal Bovine Somatotrophin (FBS), GDNF family of ligands Glialcell line-derived neurotrophic factor (GDNF), Neurturin, Persephin,Artemin, Growth differentiation factor-9 (GDF9), Hepatocyte growthfactor (HGF), Hepatoma-derived growth factor (HDGF), Insulin,Insulin-like growth factors Insulin-like, growth factor-1 (IGF-1),Insulin-like growth factor-2 (IGF-2), Interleukins IL-1-Cofactor forIL-3 and IL-6, IL-2, -3, -4, -5, -6, -7, Keratinocyte growth factor(KGF), Migration-stimulating factor (MSF), Macrophage-stimulatingprotein (MSP), also known as hepatocyte growth factor-like protein(HGFLP), Myostatin (GDF-8), Neuregulins Neuregulin 1 (NRG1), Neuregulin2 (NRG2), Neuregulin 3 (NRG3), Neuregulin 4 (NRG4), NeurotrophinsBrain-derived neurotrophic factor (BDNF), Nerve growth factor (NGF),Neurotrophin-3 (NT-3), Neurotrophin-4 (NT-4), Placental growth factor(PGF), Platelet-derived growth factor (PDGF), Renalase(RNLS)—Anti-apoptotic survival factor, T-cell growth factor (TCGF),Thrombopoietin (TPO), Transforming growth factors Transforming growthfactor alpha (TGF-α), Transforming growth factor beta (TGF-β), Tumornecrosis factor-alpha (TNF-α), Vascular endothelial growth factor(VEGF), Wnt Signaling Pathway and receptors of the same.

More specifically, a number of drug targets for human therapeuticsrepresent protein targets to which protein target moiety may be boundand incorporated into compounds according to the present invention.These include proteins which may be used to restore function in numerouspolygenic diseases, including for example B7.1 and B7, TINFR1m, TNFR2,NADPH oxidase, BclIBax and other partners in the apotosis pathway, C5areceptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IVphosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclaseinhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclo-oxygenase 1,cyclo-oxygenase 2, 5HT receptors, dopamine receptors, G Proteins, i.e.,Gq, histamine receptors, 5-lipoxygenase, tryptase serine protease,thymidylate synthase, purine nucleoside phosphorylase, GAPDHtrypanosomal, glycogen phosphorylase, Carbonic anhydrase, chemokinereceptors, JAK, STAT, RXR and similar, HIV 1 protease, HIV 1 integrase,influenza, neuramimidase, hepatitis B reverse transcriptase, sodiumchannel, multi drug resistance (MDR), protein P-glycoprotein (and MRP),tyrosine kinases, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2receptor, IL-1 receptor, TNF-alphaR, ICAM1, Cat+ channels, VCAM, VLA-4integrin, selectins, CD40/CD40L, newokinins and receptors, inosinemonophosphate dehydrogenase, p38 MAP Kinase, Ras, Raf, ERK pathway,FLT-3, KSR1, SMARCA, SMARCA2, interleukin-1 converting enzyme, caspase,HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotideformyl transferase, rhinovirus 3C protease, herpes simplex virus-1(HSV-I), protease, cytomegalovirus (CMV) protease, poly (ADP-ribose)polymerase, cyclin dependent kinases, vascular endothelial growthfactor, oxytocin receptor, microsomal transfer protein inhibitor, bileacid transport inhibitor, 5 alpha reductase inhibitors, angiotensin 11,glycine receptor, noradrenaline reuptake receptor, endothelin receptors,neuropeptide Y and receptor, estrogen receptors, androgen receptors,adenosine receptors, adenosine kinase and AMP deaminase, purinergicreceptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferases,geranylgeranyl transferase, TrkA a receptor for NGF, beta-amyloid,tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor,Her-21 neu, telomerase inhibition, cytosolic phospholipaseA2 and EGFreceptor tyrosine kinase. Additional protein targets include, forexample, ecdysone 20-monooxygenase, ion channel of the GABA gatedchloride channel, acetylcholinesterase, voltage-sensitive sodium channelprotein, calcium release channel, and chloride channels. Still furthertarget proteins include Acetyl-CoA carboxylase, adenylosuccinatesynthetase, protoporphyrinogen oxidase, andenolpyruvylshikimate-phosphate synthase.

Haloalkane dehalogenase enzymes are another target of specific compoundsaccording to the present invention. Compounds according to the presentinvention which contain chloroalkane peptide binding moieties (C1-C12often about C2-C10 alkyl halo groups) may be used to inhibit and/ordegrade haloalkane dehalogenase enzymes which are used in fusionproteins or related dioagnostic proteins as described inPCT/US2012/063401 filed Dec. 6, 2011 and published as WO 2012/078559 onJun. 14, 2012, the contents of which is incorporated by referenceherein.

These various protein targets may be used in screens that identifycompound moieties which bind to the protein and by incorporation of themoiety into compounds according to the present invention, the level ofactivity of the protein may be altered for therapeutic end result.

The compositions described below exemplify some of the members of thesetypes of small molecule target protein binding moieties. Such smallmolecule target protein binding moieties also include pharmaceuticallyacceptable salts, enantiomers, solvates and polymorphs of thesecompositions, as well as other small molecules that may target a proteinof interest. References which are cited hereinbelow are incorporated byreference herein in their entirety.

I. Heat Shock Protein 90 (HSP90) Inhibitors:

HSP90 inhibitors as used herein include, but are not limited to:

1. The HSP90 inhibitors identified in Vallee, et al., “Tricyclic Seriesof Heat Shock Protein 90 (HSP90) Inhibitors Part I: Discovery ofTricyclic Imidazo[4,5-C]Pyridines as Potent Inhibitors of the HSP90Molecular Chaperone (2011) J. Med. Chem. 54: 7206, including YKB(N-[4-(3H-imidazo[4,5-C]Pyridin-2-yl)-9H-Fluoren-9-yl]-succinamide):

derivatized where a linker group L or a -(L-MLM) group is attached, forexample, via the terminal amide group;

2. The HSP90 inhibitor p54 (modified)(8-[(2,4-dimethylphenyl)sulfanyl]-3]pent-4-yn-1-yl-3H-purin-6-amine):

derivatized where a linker group L or a -(L-MLM) group is attached, forexample, via the terminal acetylene group;

3. The HSP90 inhibitors (modified) identified in Brough, et al.,“4,5-Diarylisoxazole HSP90 Chaperone Inhibitors: Potential TherapeuticAgents for the Treatment of Cancer”, J. MED. CHEM. vol: 51, pag: 196(2008), including the compound 2GJ(5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-n-ethyl-4-[4-(morpholin-4-ylmethyl)phenyl]isoxazole-3-carboxamide)having the structure:

derivatized, where a linker group L or a -(L-MLM) group is attached, forexample, via the amide group (at the amine or at the alkyl group on theamine);

4. The HSP90 inhibitors (modified) identified in Wright, et al.,Structure-Activity Relationships in Purine-Based Inhibitor Binding toHSP90 Isoforms, Chem Biol. 2004 June; 11(6):775-85, including the HSP90inhibitor PU3 having the structure:

derivatized where a linker group L or -(L-MLM) is attached, for example,via the butyl group; and

5. The HSP90 inhibitor geldanamycin((4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1](derivatized) or any of its derivatives (e.g.17-alkylamino-17-desmethoxygeldanamycin (“17-AAG”) or17-(2-dimethylaminoethyl)amino-17-desmethoxygeldanamycin (“17-DMAG”))(derivatized, where a linker group L or a-(L-MLM) group is attached, forexample, via the amide group).

II. Kinase and Phosphatase Inhibitors:

Kinase inhibitors as used herein include, but are not limited to:

1. Erlotinib Derivative Tyrosine Kinase Inhibitor:

where R is a linker group L or a -(L-MLM) group attached, for example,via the ether group;

2. The kinase inhibitor sunitinib (derivatized):

derivatized where R is a linker group L or a -(L-MLM) group attached,for example, to the pyrrole moiety;

3. Kinase Inhibitor sorafenib (derivatized):

derivatized where R is a linker group L or a -(L-MLM) group attached,for example, to the amide moiety;

4. The kinase inhibitor desatinib (derivatized):

derivatized where R is a linker group L or a-(L-MLM) attached, forexample, to the pyrimidine;

5. The kinase inhibitor lapatinib (derivatized):

derivatized where a linker group L or a-(L-MLM) group is attached, forexample, via the terminal methyl of the sulfonyl methyl group;

6. The kinase inhibitor U09-CX-5279 (derivatized):

derivatized where a linker group L or a -(L-MLM) group is attached, forexample, via the amine (aniline), carboxylic acid or amine alpha tocyclopropyl group, or cyclopropyl group;

7. The kinase inhibitors identified in Millan, et al., Design andSynthesis of Inhaled P38 Inhibitors for the Treatment of ChronicObstructive Pulmonary Disease, J. MED. CHEM. vol: 54, pag: 7797 (2011),including the kinase inhibitors Y1W and Y1X (Derivatized) having thestructures:

YIX(1-ethyl-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridine-6-yl]sulfanyl}benzyl)urea,derivatized where a linker group L or a-(L-MLM) group is attached, forexample, via the ^(i)propyl group;

derivatized where a linker group L or a -(L-MLM) group is attached, forexample, preferably via either the i-propyl group or the t-butyl group;

8. The kinase inhibitors identified in Schenkel, et al., Discovery ofPotent and Highly Selective Thienopyridine Janus Kinase 2 Inhibitors J.Med. Chem., 2011, 54 (24), pp 8440-8450, including the compounds 6TP and0TP (Derivatized) having the structures:

derivatized where a linker group L or a -(L-MLM) group is attached, forexample, via the terminal methyl group bound to amide moiety;

derivatized where a linker group L or a -(L-MLM)group is attached, forexample, via the terminal methyl group bound to the amide moiety;

9. The kinase inhibitors identified in Van Eis, et al.,“2,6-Naphthyridines as potent and selective inhibitors of the novelprotein kinase C isozymes”, Biorg. Med. Chem. Lett. 2011 Dec. 15;21(24):7367-72, including the kinase inhibitor 07U having the structure:

derivatized where a linker group L or a -(L-MLM)group is attached, forexample, via the secondary amine or terminal amino group;

10. The kinase inhibitors identified in Lountos, et al., “StructuralCharacterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2),a Drug Target for Cancer Therapy”, J. STRUCT. BIOL. vol: 176, pag: 292(2011), including the kinase inhibitor YCF having the structure:

derivatized where a linker group L or a -(L-MLM) group is attached, forexample, via either of the terminal hydroxyl groups;

11. The kinase inhibitors identified in Lountos, et al., “StructuralCharacterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2),a Drug Target for Cancer Therapy”, J. STRUCT. BIOL. vol: 176, pag: 292(2011), including the kinase inhibitors XK9 and NXP (derivatized) havingthe structures:

derivatized where a linker group L or a -(L-MLM) group is attached, forexample, via the terminal hydroxyl group (XK9) or the hydrazone group(NXP);

12. The kinase inhibitor afatinib (derivatized)(N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide)(Derivatized where a linker group L or a -(L-MLM) group is attached, forexample, via the aliphatic amine group);

13. The kinase inhibitor fostamatinib (derivatized)([6-({5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b]-1,4-oxazin-4-yl]methyldisodium phosphate hexahydrate) (Derivatized where a linker group L or a-(L-MLM) group is attached, for example, via a methoxy group);

14. The kinase inhibitor gefitinib (derivatized)(N-(3-chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine):

derivatized where a linker group L or a -(L-MLM) group is attached, forexample, via a methoxy or ether group;

15. The kinase inhibitor lenvatinib (derivatized)(4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carboxamide)(derivatized where a linker group L or a -(L-MLM) group is attached, forexample, via the cyclopropyl group);

16. The kinase inhibitor vandetanib (derivatized)(N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine)(derivatized where a linker group L or a -(L-MLM) group is attached, forexample, via the methoxy or hydroxyl group);

17. The kinase inhibitor vemurafenib (derivatized) (propane-1-sulfonicacid{3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide),derivatized where a linker group L or a -(L-MLM) group is attached, forexample, via the sulfonyl propyl group;

18. The kinase inhibitor Gleevec (derivatized):

derivatized where R as a linker group L or a-(L-MLM) group is attached,for example, via the amide group or via the aniline amine group;

19. The kinase inhibitor pazopanib (derivatized) (VEGFR3 inhibitor):

derivatized where R is a linker group L or a -(L-MLM) group attached,for example, to the phenyl moiety or via the aniline amine group;

20. The kinase inhibitor AT-9283 (Derivatized) Aurora Kinase Inhibitor

where R is a linker group L or a -(L-MLM) group attached, for example,to the phenyl moiety);

21. The kinase inhibitor TAE684 (derivatized) ALK inhibitor

where R is a linker group L or a -(L-MLM) group attached, for example,to the phenyl moiety);

22. The kinase inhibitor nilotanib (derivatized) Abl inhibitor:

derivatized where R is a linker group L or a -(L-MLM) group attached,for example, to the phenyl moiety or the aniline amine group;

23. Kinase Inhibitor NVP-BSK805 (derivatized) JAK2 Inhibitor

derivatized where R is a linker group L or a -(L-MLM) group attached,for example, to the phenyl moiety or the diazole group;

24. Kinase Inhibitor crizotinib Derivatized Alk Inhibitor

derivatized where R is a linker group L or a -(L-MLM) group attached,for example, to the phenyl moiety or the diazole group;

25. Kinase Inhibitor JNJ FMS (derivatized) Inhibitor

derivatized where R is a linker group L or a -(L-MLM) group attached,for example, to the phenyl moiety;

26. The kinase inhibitor foretinib (derivatized) Met Inhibitor

derivatized where R is a linker group L or a -(L-MLM)group attached, forexample, to the phenyl moiety or a hydroxyl or ether group on thequinoline moiety;

27. The allosteric Protein Tyrosine Phosphatase Inhibitor PTP1B(derivatized):

derivatized where a linker group L or a -(L-MLM) group is attached, forexample, at R, as indicated;

28. The inhibitor of SHP-2 Domain of Tyrosine Phosphatase (derivatized):

derivatized where a linker group L or a -(L-MLM) group is attached, forexample, at R;

29. The inhibitor (derivatized) of BRAF (BRAF^(V600E))/MEK:

derivatized where a linker group L or a-(L-MLM) group is attached, forexample, at R;

30. Inhibitor (derivatized) of Tyrosine Kinase ABL

derivatized where a linker group L or a-(L-MLM) group is attached, forexample, at R;

31. The kinase inhibitor OSI-027 (derivatized) mTORC1/2 inhibitor

derivatized where a linker group L or a-(L-MLM) group is attached, forexample, at R;

32. The kinase inhibitor OSI-930 (derivatized) c-Kit/KDR inhibitor

derivatized where a linker group L or a-(L-MLM) group is attached, forexample, at R; and

33. The kinase inhibitor OSI-906 (derivatized) IGF1R/IR inhibitor

derivatized where a linker group L or a-(L-MLM) group is attached, forexample, at R.

Wherein, in any of the embodiments described in sections I-XVII, “R”designates a site for attachment of a linker group L or a -(L-MLM)groupon the piperazine moiety.

III. HDM2/MDM2 Inhibitors:

HDM2/MDM2 inhibitors as used herein include, but are not limited to:

1. The HDM2/MDM2 inhibitors identified in Vassilev, et al., In vivoactivation of the p53 pathway by small-molecule antagonists of MDM2,SCIENCE vol: 303, pag: 844-848 (2004), and Schneekloth, et al., Targetedintracellular protein degradation induced by a small molecule: En routeto chemical proteomics, Bioorg. Med. Chem. Lett. 18 (2008) 5904-5908,including (or additionally) the compounds nutlin-3, nutlin-2, andnutlin-1 (derivatized) as described below, as well as all derivativesand analogs thereof:

(derivatized where a linker group L or a -(L-MLM)group is attached, forexample, at the methoxy group or as a hydroxyl group);

(derivatized where a linker group L or a -(L-MLM) group is attached, forexample, at the methoxy group or hydroxyl group);

(derivatized where a linker group L or a -(L-MLM) group is attached, forexample, via the methoxy group or as a hydroxyl group); and

2. Trans-4-Iodo-4′-Boranyl-Chalcone

(derivatized where a linker group L or a a linker group L or a-(L-MLM)group is attached, for example, via a hydroxy group).

IV. Compounds Targeting Human BET Bromodomain-Containing Proteins:

In certain embodiments, “PTM” can be ligands binding to Bromo- andExtra-terminal (BET) proteins BRD2, BRD3 and BRD4. Compounds targetingHuman BET Bromodomain-containing proteins include, but are not limitedto the compounds associated with the targets as described below, where“R” or “linker” designates a site for linker group L or a-(L-MLM) groupattachment, for example:

1. JQ1, Filippakopoulos et al. Selective inhibition of BET bromodomains.Nature (2010):

2. I-BET, Nicodeme et al. Supression of Inflammation by a SyntheticHistone Mimic. Nature (2010). Chung et al. Discovery andCharacterization of Small Molecule Inhibitors of the BET FamilyBromodomains. J. Med Chem. (2011):

3. Compounds described in Hewings et al. 3,5-Dimethylisoxazoles Act asAcetyl-lysine Bromodomain Ligands. J. Med. Chem. (2011) 54 6761-6770.

4. I-BET151, Dawson et al. Inhibition of BET Recruitment to Chromatin asan Efective Treatment for MLL-fusion Leukemia. Nature (2011):

5. Carbazole type (US 2015/0256700)

6. Pyrrolopyridone type (US 2015/0148342)

7. Tetrahydroquinoline type (WO 2015/074064)

8. Triazolopyrazine type (WO 2015/067770)

9. Pyridone type (WO 2015/022332)

10. Quinazolinone type (WO 2015/015318)

11. Dihydropyridopyrazinone type (WO 2015/011084)

V. HDAC Inhibitors:

HDAC Inhibitors (derivatized) include, but are not limited to:

1. Finnin, M. S. et al. Structures of Histone Deacetylase HomologueBound to the TSA and SAHA Inhibitors. Nature 40, 188-193 (1999).

(Derivatized where “R” designates a site for attachment, for example, ofa linker group L or a -(L-MLM) group); and

2. Compounds as defined by formula (I) of PCT WO0222577 (“DEACETYLASEINHIBITORS”) (Derivatized where a linker group L or a -(L-MLM) group isattached, for example, via the hydroxyl group);

VI. Human Lysine Methyltransferase Inhibitors:

Human Lysine Methyltransferase inhibitors include, but are not limitedto:

1. Chang et al. Structural Basis for G9a-Like protein LysineMethyltransferase Inhibition by BIX-1294. Nat. Struct. Biol. (2009)16(3) 312.

(Derivatized where “R” designates a site for attachment, for example, ofa linker group L or a -(L-MLM) group);

2. Liu, F. et al Discovery of a 2,4-Diamino-7-aminoalkoxyquinazoline asa Potent and Selective Inhibitor of Histone Methyltransferase G9a. J.Med. Chem. (2009) 52(24) 7950.

(Derivatized where “R” designates a potential site for attachment, forexample, of a linker group L or a -(L-MLM) group);

3. Azacitidine (derivatized)(4-amino-1-β-D-ribofuranosyl-1,3,5-triazin-2(1H)-one) (Derivatized wherea linker group L or a -(L-MLM) group is attached, for example, via thehydroxy or amino groups); and

4. Decitabine (derivatized)(4-amino-1-(2-deoxy-b-D-erythro-pentofuranosyl)-1, 3,5-triazin-2(1H)-one) (Derivatized where a linker group L or a -(L-MLM)group is attached, for example, via either of the hydroxy groups or atthe amino group).

VII. Angiogenesis Inhibitors:

Angiogenesis inhibitors include, but are not limited to:

1. GA-1 (derivatized) and derivatives and analogs thereof, having thestructure(s) and binding to linkers as described in Sakamoto, et al.,Development of Protacs to target cancer-promoting proteins forubiquitination and degradation, Mol Cell Proteomics 2003 December;2(12):1350-8;

2. Estradiol (derivatized), which may be bound to a linker group L or a-(L-MLM) group as is generally described in Rodriguez-Gonzalez, et al.,Targeting steroid hormone receptors for ubiquitination and degradationin breast and prostate cancer, Oncogene (2008) 27, 7201-7211;

3. Estradiol, testosterone (derivatized) and related derivatives,including but not limited to DHT and derivatives and analogs thereof,having the structure(s) and binding to a linker group L or a -(L-MLM)group as generally described in Sakamoto, et al., Development of Protacsto target cancer-promoting proteins for ubiquitination and degradation,Mol Cell Proteomics 2003 December; 2(12):1350-8; and

4. Ovalicin, fumagillin (derivatized), and derivatives and analogsthereof, having the structure(s) and binding to a linker group L or a-(L-MLM) group as is generally described in Sakamoto, et al., Protacs:chimeric molecules that target proteins to the Skp1-Cullin-F box complexfor ubiquitination and degradation Proc Natl Acad Sci USA. 2001 Jul. 17;98(15):8554-9 and U.S. Pat. No. 7,208,157.

VIII. Immunosuppressive Compounds:

Immunosuppressive compounds include, but are not limited to:

1. AP21998 (derivatized), having the structure(s) and binding to alinker group L or a -(L-MLM) group as is generally described inSchneekloth, et al., Chemical Genetic Control of Protein Levels:Selective in Vivo Targeted Degradation, J. AM. CHEM. SOC. 2004, 126,3748-3754;

2. Glucocorticoids (e.g., hydrocortisone, prednisone, prednisolone, andmethylprednisolone) (Derivatized where a linker group L or a -(L-MLM)group is to bound, e.g. to any of the hydroxyls) and beclometasonedipropionate (Derivatized where a linker group or a -(L-MLM) is bound,e.g. to a proprionate);

3. Methotrexate (Derivatized where a linker group or a -(L-MLM) groupcan be bound, e.g. to either of the terminal hydroxyls);

4. Ciclosporin (Derivatized where a linker group or a -(L-MLM) group canbe bound, e.g. at any of the butyl groups);

5. Tacrolimus (FK-506) and rapamycin (Derivatized where a linker group Lor a -(L-MLM) group can be bound, e.g. at one of the methoxy groups);and

6. Actinomycins (Derivatized where a linker group L or a -(L-MLM) groupcan be bound, e.g. at one of the isopropyl groups).

IX. Compounds Targeting the Aryl Hydrocarbon Receptor (AHR):

Compounds targeting the aryl hydrocarbon receptor (AHR) include, but arenot limited to:

1. Apigenin (Derivatized in a way which binds to a linker group L or a-(L-MLM) group as is generally illustrated in Lee, et al., TargetedDegradation of the Aryl Hydrocarbon Receptor by the PROTAC Approach: AUseful Chemical Genetic Tool, ChemBioChem Volume 8, Issue 17, pages2058-2062, Nov. 23, 2007); and

2. SR1 and LGC006 (derivatized such that a linker group L or a -(L-MLM)is bound), as described in Boitano, et al., Aryl Hydrocarbon ReceptorAntagonists Promote the Expansion of Human Hematopoietic Stem Cells,Science 10 Sep. 2010: Vol. 329 no. 5997 pp. 1345-1348.

X. Compounds Targeting RAF Receptor (Kinase):

(Derivatized where “R” designates a site for linker group L or -(L-MLM)group attachment, for example).

XI. Compounds Targeting FKBP:

(Derivatized where “R” designates a site for a linker group L or a-(L-MLM) group attachment, for example).

XII. Compounds Targeting Androgen Receptor (AR)

1. RU59063 Ligand (derivatized) of Androgen Rceptor

(Derivatized where “R” designates a site for a linker group L or a-(L-MLM) group attachment, for example).

2. SARM Ligand (derivatized) of Androgen Receptor

(Derivatized where “R” designates a site for a linker group L ora-(L-MLM) group attachment, for example).

3. Androgen Receptor Ligand DHT (derivatized)

(Derivatized where “R” designates a site for a linker group L or-(L-MLM) group attachment, for example).

4. MDV3100 Ligand (derivatized)

5. ARN-509 Ligand (derivatized)

6. Hexahydrobenzisoxazoles

7. Tetramethylcyclobutanes

XIII. Compounds Targeting Estrogen Receptor (ER) ICI-182780

1. Estrogen Receptor Ligand

(Derivatized where “R” designates a site for linker group L or -(L-MLM)group attachment).

XIV. Compounds Targeting Thyroid Hormone Receptor (TR)

1. Thyroid Hormone Receptor Ligand (derivatized)

(Derivatized where “R” designates a site for linker group L or -(L-MLM)group attachment and MOMO indicates a methoxymethoxy group).

XV. Compounds Targeting HIV Protease

1. Inhibitor of HIV Protease (derivatized)

(Derivatized where “R” designates a site for linker group L or -(L-MLM)group attachment). See, J. Med. Chem. 2010, 53, 521-538.

2. Inhibitor of HIV Protease

(Derivatized where “R” designates a potential site for linker group L or-(L-MLM) group attachment). See, J. Med. Chem. 2010, 53, 521-538.

XVI. Compounds Targeting HIV Integrase

1. Inhibitor of HIV Integrase (derivatized)

(Derivatized where “R” designates a site for linker group L or -(L-MLM)group attachment). See, J. Med. Chem. 2010, 53, 6466.

2. Inhibitor of HIV Integrase (derivatized)

3. Inhibitor of HIV integrase Isetntress (derivatized)

(Derivatized where “R” designates a site for linker group L or -(L-MLM)group attachment). See, J. Med. Chem. 2010, 53, 6466.

XVII. Compounds Targeting HCV Protease

1. Inhibitors of HCV Protease (derivatized)

(Derivatized where “R” designates a site for linker group L or -(L-MLM)group attachment).

XVIII. Compounds Targeting Acyl-Protein Thioesterase-1 and -2 (APT1 andAPT2)

1. Inhibitor of APT1 and APT2 (derivatized)

(Derivatized where “R” designates a site for linker group L or -(L-MLM)group attachment). See, Angew. Chem. Int. Ed. 2011, 50, 9838-9842, whereL is a linker group as otherwise described herein and said MLM group isas otherwise described herein such that -(L-MLM) binds the MLM group toa PTM group as otherwise described herein.

Therapeutic Compositions

Pharmaceutical compositions comprising combinations of an effectiveamount of at least one bifunctional compound as described herein, andone or more of the compounds otherwise described herein, all ineffective amounts, in combination with a pharmaceutically effectiveamount of a carrier, additive or excipient, represents a further aspectof the present disclosure.

The present disclosure includes, where applicable, the compositionscomprising the pharmaceutically acceptable salts, in particular, acid orbase addition salts of compounds as described herein. The acids whichare used to prepare the pharmaceutically acceptable acid addition saltsof the aforementioned base compounds useful according to this aspect arethose which form non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as the hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, acetate, lactate, citrate, acid citrate, tartrate,bitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3naphthoate)]salts, among numerous others.

Pharmaceutically acceptable base addition salts may also be used toproduce pharmaceutically acceptable salt forms of the compounds orderivatives according to the present disclosure. The chemical bases thatmay be used as reagents to prepare pharmaceutically acceptable basesalts of the present compounds that are acidic in nature are those thatform non-toxic base salts with such compounds. Such non-toxic base saltsinclude, but are not limited to those derived from suchpharmacologically acceptable cations such as alkali metal cations (eg.,potassium and sodium) and alkaline earth metal cations (eg, calcium,zinc and magnesium), ammonium or water-soluble amine addition salts suchas N-methylglucamine-(meglumine), and the lower alkanolammonium andother base salts of pharmaceutically acceptable organic amines, amongothers.

The compounds as described herein may, in accordance with thedisclosure, be administered in single or divided doses by the oral,parenteral or topical routes. Administration of the active compound mayrange from continuous (intravenous drip) to several oral administrationsper day (for example, Q.I.D.) and may include oral, topical, parenteral,intramuscular, intravenous, sub-cutaneous, transdermal (which mayinclude a penetration enhancement agent), buccal, sublingual andsuppository administration, among other routes of administration.Enteric coated oral tablets may also be used to enhance bioavailabilityof the compounds from an oral route of administration. The mosteffective dosage form will depend upon the pharmacokinetics of theparticular agent chosen as well as the severity of disease in thepatient. Administration of compounds according to the present disclosureas sprays, mists, or aerosols for intra-nasal, intra-tracheal orpulmonary administration may also be used. The present disclosuretherefore also is directed to pharmaceutical compositions comprising aneffective amount of compound as described herein, optionally incombination with a pharmaceutically acceptable carrier, additive orexcipient. Compounds according to the present disclosureion may beadministered in immediate release, intermediate release or sustained orcontrolled release forms. Sustained or controlled release forms arepreferably administered orally, but also in suppository and transdermalor other topical forms. Intramuscular injections in liposomal form mayalso be used to control or sustain the release of compound at aninjection site.

The compositions as described herein may be formulated in a conventionalmanner using one or more pharmaceutically acceptable carriers and mayalso be administered in controlled-release formulations.Pharmaceutically acceptable carriers that may be used in thesepharmaceutical compositions include, but are not limited to, ionexchangers, alumina, aluminum stearate, lecithin, serum proteins, suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as prolaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

The compositions as described herein may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously.

Sterile injectable forms of the compositions as described herein may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1, 3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such as Ph. Helv orsimilar alcohol.

The pharmaceutical compositions as described herein may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers which are commonly used includelactose and corn starch. Lubricating agents, such as magnesium stearate,are also typically added. For oral administration in a capsule form,useful diluents include lactose and dried corn starch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions as described herein maybe administered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient, which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions as described herein may also beadministered topically. Suitable topical formulations are readilyprepared for each of these areas or organs. Topical application for thelower intestinal tract can be effected in a rectal suppositoryformulation (see above) or in a suitable enema formulation.Topically-acceptable transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. In certain preferred aspects of the invention, the compounds maybe coated onto a stent which is to be surgically implanted into apatient in order to inhibit or reduce the likelihood of occlusionoccurring in the stent in the patient.

Alternatively, the pharmaceutical compositions can be formulated in asuitable lotion or cream containing the active components suspended ordissolved in one or more pharmaceutically acceptable carriers. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith our without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions as described herein may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

The amount of compound in a pharmaceutical composition as describedherein that may be combined with the carrier materials to produce asingle dosage form will vary depending upon the host and diseasetreated, the particular mode of administration. Preferably, thecompositions should be formulated to contain between about 0.05milligram to about 750 milligrams or more, more preferably about 1milligram to about 600 milligrams, and even more preferably about 10milligrams to about 500 milligrams of active ingredient, alone or incombination with at least one other compound according to the presentinvention.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease or condition beingtreated.

A patient or subject in need of therapy using compounds according to themethods described herein can be treated by administering to the patient(subject) an effective amount of the compound according to the presentinvention including pharmaceutically acceptable salts, solvates orpolymorphs, thereof optionally in a pharmaceutically acceptable carrieror diluent, either alone, or in combination with other knownerythopoiesis stimulating agents as otherwise identified herein.

These compounds can be administered by any appropriate route, forexample, orally, parenterally, intravenously, intradermally,subcutaneously, or topically, including transdermally, in liquid, cream,gel, or solid form, or by aerosol form.

The active compound is included in the pharmaceutically acceptablecarrier or diluent in an amount sufficient to deliver to a patient atherapeutically effective amount for the desired indication, withoutcausing serious toxic effects in the patient treated. A preferred doseof the active compound for all of the herein-mentioned conditions is inthe range from about 10 ng/kg to 300 mg/kg, preferably 0.1 to 100 mg/kgper day, more generally 0.5 to about 25 mg per kilogram body weight ofthe recipient/patient per day. A typical topical dosage will range from0.01-5% wt/wt in a suitable carrier.

The compound is conveniently administered in any suitable unit dosageform, including but not limited to one containing less than 1 mg, 1 mgto 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosageform. An oral dosage of about 25-250 mg is often convenient.

The active ingredient is preferably administered to achieve peak plasmaconcentrations of the active compound of about 0.00001-30 mM, preferablyabout 0.1-30 μM. This may be achieved, for example, by the intravenousinjection of a solution or formulation of the active ingredient,optionally in saline, or an aqueous medium or administered as a bolus ofthe active ingredient. Oral administration is also appropriate togenerate effective plasma concentrations of active agent.

The concentration of active compound in the drug composition will dependon absorption, distribution, inactivation, and excretion rates of thedrug as well as other factors known to those of skill in the art. It isto be noted that dosage values will also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed composition. The active ingredient may be administered atonce, or may be divided into a number of smaller doses to beadministered at varying intervals of time.

Oral compositions will generally include an inert diluent or an ediblecarrier. They may be enclosed in gelatin capsules or compressed intotablets. For the purpose of oral therapeutic administration, the activecompound or its prodrug derivative can be incorporated with excipientsand used in the form of tablets, troches, or capsules. Pharmaceuticallycompatible binding agents, and/or adjuvant materials can be included aspart of the composition.

The tablets, pills, capsules, troches and the like can contain any ofthe following ingredients, or compounds of a similar nature: a bindersuch as microcrystalline cellulose, gum tragacanth or gelatin; anexcipient such as starch or lactose, a dispersing agent such as alginicacid, Primogel, or corn starch; a lubricant such as magnesium stearateor Sterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring. When the dosage unitform is a capsule, it can contain, in addition to material of the abovetype, a liquid carrier such as a fatty oil. In addition, dosage unitforms can contain various other materials which modify the physical formof the dosage unit, for example, coatings of sugar, shellac, or entericagents.

The active compound or pharmaceutically acceptable salt thereof can beadministered as a component of an elixir, suspension, syrup, wafer,chewing gum or the like. A syrup may contain, in addition to the activecompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors.

The active compound or pharmaceutically acceptable salts thereof canalso be mixed with other active materials that do not impair the desiredaction, or with materials that supplement the desired action, such aserythropoietin stimulating agents, including EPO and darbapoietin alfa,among others. In certain preferred aspects of the invention, one or morecompounds according to the present invention are coadministered withanother bioactive agent, such as an erythropoietin stimulating agent ora would healing agent, including an antibiotic, as otherwise describedherein.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include the following components: a sterilediluent such as water for injection, saline solution, fixed oils,polyethylene glycols, glycerine, propylene glycol or other syntheticsolvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parental preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic.

If administered intravenously, preferred carriers are physiologicalsaline or phosphate buffered saline (PBS).

In one embodiment, the active compounds are prepared with carriers thatwill protect the compound against rapid elimination from the body, suchas a controlled release formulation, including implants andmicroencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art.

Liposomal suspensions may also be pharmaceutically acceptable carriers.These may be prepared according to methods known to those skilled in theart, for example, as described in U.S. Pat. No. 4,522,811 (which isincorporated herein by reference in its entirety). For example, liposomeformulations may be prepared by dissolving appropriate lipid(s) (such asstearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline,arachadoyl phosphatidyl choline, and cholesterol) in an inorganicsolvent that is then evaporated, leaving behind a thin film of driedlipid on the surface of the container. An aqueous solution of the activecompound are then introduced into the container. The container is thenswirled by hand to free lipid material from the sides of the containerand to disperse lipid aggregates, thereby forming the liposomalsuspension.

Therapeutic Methods

In an additional aspect, the description provides therapeuticcompositions comprising an effective amount of a compound as describedherein or salt form thereof, and a pharmaceutically acceptable carrier.The therapeutic compositions modulate protein degradation in a patientor subject, for example, an animal such as a human, and can be used fortreating or ameliorating disease states or conditions which aremodulated through the degraded protein.

The terms “treat”, “treating”, and “treatment”, etc., as used herein,refer to any action providing a benefit to a patient for which thepresent compounds may be administered, including the treatment of anydisease state or condition which is modulated through the protein towhich the present compounds bind. Disease states or conditions,including cancer, which may be treated using compounds according to thepresent invention are set forth hereinabove.

The description provides therapeutic compositions as described hereinfor effectuating the degradation of proteins of interest for thetreatment or amelioration of a disease, e.g., cancer. In certainadditional embodiments, the disease is multiple myeloma. As such, inanother aspect, the description provides a method ofubiquitinating/degrading a target protein in a cell. In certainembodiments, the method comprises administering a bifunctional compoundas described herein comprising, e.g., a MLM and a PTM, preferably linkedthrough a linker moiety, as otherwise described herein, wherein the MLMis coupled to the PTM and wherein the MLM recognizes a ubiquitin pathwayprotein (e.g., an ubiquitin ligase, preferably an E3 ubiquitin ligasesuch as, e.g., cereblon) and the PTM recognizes the target protein suchthat degradation of the target protein will occur when the targetprotein is placed in proximity to the ubiquitin ligase, thus resultingin degradation/inhibition of the effects of the target protein and thecontrol of protein levels. The control of protein levels afforded by thepresent invention provides treatment of a disease state or condition,which is modulated through the target protein by lowering the level ofthat protein in the cell, e.g., cell of a patient. In certainembodiments, the method comprises administering an effective amount of acompound as described herein, optionally including a pharamaceuticallyacceptable excipient, carrier, adjuvant, another bioactive agent orcombination thereof.

In additional embodiments, the description provides methods for treatingor emeliorating a disease, disorder or symptom thereof in a subject or apatient, e.g., an animal such as a human, comprising administering to asubject in need thereof a composition comprising an effective amount,e.g., a therapeutically effective amount, of a compound as describedherein or salt form thereof, and a pharmaceutically acceptableexcipient, carrier, adjuvant, another bioactive agent or combinationthereof, wherein the composition is effective for treating orameliorating the disease or disorder or symptom thereof in the subject.

In another aspect, the description provides methods for identifying theeffects of the degradation of proteins of interest in a biologicalsystem using compounds according to the present invention.

In another embodiment, the present invention is directed to a method oftreating a human patient in need for a disease state or conditionmodulated through a protein where the degradation of that protein willproduce a therapeutic effect in that patient, the method comprisingadministering to a patient in need an effective amount of a compoundaccording to the present invention, optionally in combination withanother bioactive agent. The disease state or condition may be a diseasecaused by a microbial agent or other exogenous agent such as a virus,bacteria, fungus, protozoa or other microbe or may be a disease state,which is caused by overexpression of a protein, which leads to a diseasestate and/or condition

The term “disease state or condition” is used to describe any diseasestate or condition wherein protein dysregulation (i.e., the amount ofprotein expressed in a patient is elevated) occurs and where degradationof one or more proteins in a patient may provide beneficial therapy orrelief of symptoms to a patient in need thereof. In certain instances,the disease state or condition may be cured.

Disease states of conditions which may be treated using compoundsaccording to the present invention include, for example, asthma,autoimmune diseases such as multiple sclerosis, various cancers,ciliopathies, cleft palate, diabetes, heart disease, hypertension,inflammatory bowel disease, mental retardation, mood disorder, obesity,refractive error, infertility, Angelman syndrome, Canavan disease,Coeliac disease, Charcot-Marie-Tooth disease, Cystic fibrosis, Duchennemuscular dystrophy, Haemochromatosis, Haemophilia, Klinefelter'ssyndrome, Neurofibromatosis, Phenylketonuria, Polycystic kidney disease,(PKD1) or 4 (PKD2) Prader-Willi syndrome, Sickle-cell disease, Tay-Sachsdisease, Turner syndrome.

Further disease states or conditions which may be treated by compoundsaccording to the present invention include Alzheimer's disease,Amyotrophic lateral sclerosis (Lou Gehrig's disease), Anorexia nervosa,Anxiety disorder, Atherosclerosis, Attention deficit hyperactivitydisorder, Autism, Bipolar disorder, Chronic fatigue syndrome, Chronicobstructive pulmonary disease, Crohn's disease, Coronary heart disease,Dementia, Depression, Diabetes mellitus type 1, Diabetes mellitus type2, Epilepsy, Guillain-Barré syndrome, Irritable bowel syndrome, Lupus,Metabolic syndrome, Multiple sclerosis, Myocardial infarction, Obesity,Obsessive-compulsive disorder, Panic disorder, Parkinson's disease,Psoriasis, Rheumatoid arthritis, Sarcoidosis, Schizophrenia, Stroke,Thromboangiitis obliterans, Tourette syndrome, Vasculitis.

Still additional disease states or conditions which can be treated bycompounds according to the present invention include aceruloplasminemia,Achondrogenesis type II, achondroplasia, Acrocephaly, Gaucher diseasetype 2, acute intermittent porphyria, Canavan disease, AdenomatousPolyposis Coli, ALA dehydratase deficiency, adenylosuccinate lyasedeficiency, Adrenogenital syndrome, Adrenoleukodystrophy, ALA-Dporphyria, ALA dehydratase deficiency, Alkaptonuria, Alexander disease,Alkaptonuric ochronosis, alpha 1-antitrypsin deficiency, alpha-1proteinase inhibitor, emphysema, amyotrophic lateral sclerosis Alströmsyndrome, Alexander disease, Amelogenesis imperfecta, ALA dehydratasedeficiency, Anderson-Fabry disease, androgen insensitivity syndrome,Anemia Angiokeratoma Corporis Diffusum, Angiomatosis retinae (vonHippel-Lindau disease) Apert syndrome, Arachnodactyly (Marfan syndrome),Stickler syndrome, Arthrochalasis multiplex congenital (Ehlers-Danlossyndrome#arthrochalasia type) ataxia telangiectasia, Rett syndrome,primary pulmonary hypertension, Sandhoff disease, neurofibromatosis typeII, Beare-Stevenson cutis gyrata syndrome, Mediterranean fever,familial, Benjamin syndrome, beta-thalassemia, Bilateral AcousticNeurofibromatosis (neurofibromatosis type II), factor V Leidenthrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloomsyndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich syndrome(Turner syndrome), Bourneville disease (tuberous sclerosis), priondisease, Birt-Hogg-Dubé syndrome, Brittle bone disease (osteogenesisimperfecta), Broad Thumb-Hallux syndrome (Rubinstein-Taybi syndrome),Bronze Diabetes/Bronzed Cirrhosis (hemochromatosis), Bulbospinalmuscular atrophy (Kennedy's disease), Burger-Grutz syndrome (lipoproteinlipase deficiency), CGD Chronic granulomatous disorder, Campomelicdysplasia, biotinidase deficiency, Cardiomyopathy (Noonan syndrome), Cridu chat, CAVD (congenital absence of the vas deferens), Caylorcardiofacial syndrome (CBAVD), CEP (congenital erythropoieticporphyria), cystic fibrosis, congenital hypothyroidism, Chondrodystrophysyndrome (achondroplasia), otospondylomegaepiphyseal dysplasia,Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome,Thanatophoric dysplasia, Coffin-Lowry syndrome, Cockayne syndrome,(familial adenomatous polyposis), Congenital erythropoietic porphyria,Congenital heart disease, Methemoglobinemia/Congenitalmethaemoglobinaemia, achondroplasia, X-linked sideroblastic anemia,Connective tissue disease, Conotruncal anomaly face syndrome, Cooley'sAnemia (beta-thalassemia), Copper storage disease (Wilson's disease),Copper transport disease (Menkes disease), hereditary coproporphyria,Cowden syndrome, Craniofacial dysarthrosis (Crouzon syndrome),Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowdensyndrome, Curschmann-Batten-Steinert syndrome (myotonic dystrophy),Beare-Stevenson cutis gyrata syndrome, primary hyperoxaluria,spondyloepimetaphyseal dysplasia (Strudwick type), muscular dystrophy,Duchenne and Becker types (DBMD), Usher syndrome, Degenerative nervediseases including de Grouchy syndrome and Dejerine-Sottas syndrome,developmental disabilities, distal spinal muscular atrophy, type V,androgen insensitivity syndrome, Diffuse Globoid Body Sclerosis (Krabbedisease), Di George's syndrome, Dihydrotestosterone receptor deficiency,androgen insensitivity syndrome, Down syndrome, Dwarfism, erythropoieticprotoporphyria Erythroid 5-aminolevulinate synthetase deficiency,Erythropoietic porphyria, erythropoietic protoporphyria, erythropoieticuroporphyria, Friedreich's ataxia, familial paroxysmal polyserositis,porphyria cutanea tarda, familial pressure sensitive neuropathy, primarypulmonary hypertension (PPH), Fibrocystic disease of the pancreas,fragile X syndrome, galactosemia, genetic brain disorders, Giant cellhepatitis (Neonatal hemochromatosis), Gronblad-Strandberg syndrome(pseudoxanthoma elasticum), Gunther disease (congenital erythropoieticporphyria), haemochromatosis, Hallgren syndrome, sickle cell anemia,hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-Lindau disease(von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilfordprogeria syndrome (progeria), Hyperandrogenism, Hypochondroplasia,Hypochromic anemia, Immune system disorders, including X-linked severecombined immunodeficiency, Insley-Astley syndrome, Jackson-Weisssyndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson-Weisssyndrome, Kidney diseases, including hyperoxaluria, Klinefelter'ssyndrome, Kniest dysplasia, Lacunar dementia, Langer-Saldinoachondrogenesis, ataxia telangiectasia, Lynch syndrome,Lysyl-hydroxylase deficiency, Machado-Joseph disease, Metabolicdisorders, including Kniest dysplasia, Marfan syndrome, Movementdisorders, Mowat-Wilson syndrome, cystic fibrosis, Muenke syndrome,Multiple neurofibromatosis, Nance-Insley syndrome, Nance-Sweeneychondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffersyndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, Polycystickidney disease, polyostotic fibrous dysplasia (McCune-Albrightsyndrome), Peutz-Jeghers syndrome, Prader-Labhart-Willi syndrome,hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome),primary pulmonary hypertension, primary senile degenerative dementia,prion disease, progeria (Hutchinson Gilford Progeria Syndrome),progressive chorea, chronic hereditary (Huntington) (Huntington'sdisease), progressive muscular atrophy, spinal muscular atrophy,propionic acidemia, protoporphyria, proximal myotonic dystrophy,pulmonary arterial hypertension, PXE (pseudoxanthoma elasticum), Rb(retinoblastoma), Recklinghausen disease (neurofibromatosis type I),Recurrent polyserositis, Retinal disorders, Retinoblastoma, Rettsyndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome, Roussy-Levysyndrome, severe achondroplasia with developmental delay and acanthosisnigricans (SADDAN), Li-Fraumeni syndrome, sarcoma, breast, leukemia, andadrenal gland (SBLA) syndrome, sclerosis tuberose (tuberous sclerosis),SDAT, SED congenital (spondyloepiphyseal dysplasia congenita), SEDStrudwick (spondyloepimetaphyseal dysplasia, Strudwick type), SEDc(spondyloepiphyseal dysplasia congenita) SEMD, Strudwick type(spondyloepimetaphyseal dysplasia, Strudwick type), Shprintzen syndrome,Skin pigmentation disorders, Smith-Lemli-Opitz syndrome, South-Africangenetic porphyria (variegate porphyria), infantile-onset ascendinghereditary spastic paralysis, Speech and communication disorders,sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Sticklersyndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterindeficiency, beta-thalassemia, Thyroid disease, Tomaculous neuropathy(hereditary neuropathy with liability to pressure palsies), TreacherCollins syndrome, Triplo X syndrome (triple X syndrome), Trisomy 21(Down syndrome), Trisomy X, VHL syndrome (von Hippel-Lindau disease),Vision impairment and blindness (Alström syndrome), Vrolik disease,Waardenburg syndrome, Warburg Sjo Fledelius Syndrome, Weissenbacher-Zweymüller syndrome, Wolf-Hirschhorn syndrome, Wolff Periodicdisease, Weis senbacher-Zweymüller syndrome and Xeroderma pigmentosum,among others.

The term “neoplasia” or “cancer” is used throughout the specification torefer to the pathological process that results in the formation andgrowth of neoplasm, i.e., abnormal tissue that grows by cellularproliferation, often more rapidly than normal and continues to growafter the stimuli that initiated the new growth cease. Malignantneoplasms show partial or complete lack of structural organization andfunctional coordination with the normal tissue and most invadesurrounding tissues, metastasize to several sites, and are likely torecur after attempted removal and to cause the death of the patientunless adequately treated. As used herein, the term neoplasia is used todescribe all cancerous disease states and embraces or encompasses thepathological process associated with malignant hematogenous, ascitic andsolid tumors. Exemplary cancers which may be treated by the presentcompounds either alone or in combination with at least one additionalanti-cancer agent include squamous-cell carcinoma, basal cell carcinoma,adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas,cancer of the bladder, bowel, breast, cervix, colon, esophagus, head,kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach;leukemias; benign and malignant lymphomas, particularly Burkitt'slymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas;myeloproliferative diseases; sarcomas, including Ewing's sarcoma,hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheralneuroepithelioma, synovial sarcoma, gliomas, astrocytomas,oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas,ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors,meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowelcancer, breast cancer, prostate cancer, cervical cancer, uterine cancer,lung cancer, ovarian cancer, testicular cancer, thyroid cancer,astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, livercancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease,Wilms' tumor and teratocarcinomas. Additional cancers which may betreated using compounds according to the present invention include, forexample, T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineagelymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cellLeukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, BurkittsLymphoma, B-cell ALL, Philadelphia chromosome positive ALL andPhiladelphia chromosome positive CML.

The term “bioactive agent” is used to describe an agent, other than acompound according to the present invention, which is used incombination with the present compounds as an agent with biologicalactivity to assist in effecting an intended therapy, inhibition and/orprevention/prophylaxis for which the present compounds are used.Preferred bioactive agents for use herein include those agents whichhave pharmacological activity similar to that for which the presentcompounds are used or administered and include for example, anti-canceragents, antiviral agents, especially including anti-HIV agents andanti-HCV agents, antimicrobial agents, antifungal agents, etc.

The term “anti-cancer agent” is used to describe an anti-cancer agent,which may be incorporated into the bifunctional compounds according tothe present invention or incombination with the same to treat cancer.These agents include, for example, everolimus, trabectedin, abraxane,TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin,vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, aFLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurorakinase inhibitor, a PIK-1 modulator, a Bcl-2 inhibitor, an HDACinhbitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an EGFRTK inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a PI3 kinaseinhibitor, an AKT inhibitor, an mTORC1/2 inhibitor, a JAK/STATinhibitor, a checkpoint-1 or 2 inhibitor, a focal adhesion kinaseinhibitor, a Map kinase kinase (mek) inhibitor, a VEGF trap antibody,pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab,amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin,ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan,tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111,131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan,IL13-PE38QQR, INO 1001, IPdR₁ KRX-0402, lucanthone, LY317615, neuradiab,vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin,ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide,gemcitabine, doxorubicin, liposomal doxorubicin,5′-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709,seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid,N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-,disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan,tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen,bevacizumab, IMC-1C11, CHIR-258);3-[5-(methylsulfonylpiperadinemethyl)-indolyl-quinolone, vatalanib,AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelinpamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate,megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide,megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib,canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016,Ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanalide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248,sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide,L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin,bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil,cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine,dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine,fludrocortisone, fluoxymesterone, flutamide, gleevec, gemcitabine,hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole,lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna,methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide,oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer,procarbazine, raltitrexed, rituximab, streptozocin, teniposide,testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine,13-cis-retinoic acid, phenylalanine mustard, uracil mustard,estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosinearabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin,mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat,COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668,EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene,idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab,denileukin diftitox, gefitinib, bortezimib, paclitaxel, cremophor-freepaclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705,droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene,fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339,ZK186619, topotecan, PTK787/ZK 222584, VX-745, PD 184352, rapamycin,40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001,ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646,wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin,erythropoietin, granulocyte colony-stimulating factor, zolendronate,prednisone, cetuximab, granulocyte macrophage colony-stimulating factor,histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylatedinterferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase,lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane,alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2,megestrol, immune globulin, nitrogen mustard, methylprednisolone,ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine,bexarotene, tositumomab, arsenic trioxide, cortisone, editronate,mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase,strontium 89, casopitant, netupitant, an NK-1 receptor antagonist,palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide,lorazepam, alprazolam, haloperidol, droperidol, dronabinol,dexamethasone, methylprednisolone, prochlorperazine, granisetron,ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin,epoetin alfa, darbepoetin alfa and mixtures thereof.

The term “anti-HIV agent” includes, for example, nucleoside reversetranscriptase inhibitors (NRTI), other non-nucloeoside reversetranscriptase inhibitors (i.e., those which are not representative ofthe present invention), protease inhibitors, fusion inhibitors, amongothers, exemplary compounds of which may include, for example, 3TC(Lamivudine), AZT (Zidovudine), (−)-FTC, ddl (Didanosine), ddC(zalcitabine), abacavir (ABC), tenofovir (PMPA), D-D4FC (Reverset), D4T(Stavudine), Racivir, L-FddC, L-FD4C, NVP (Nevirapine), DLV(Delavirdine), EFV (Efavirenz), SQVM (Saquinavir mesylate), RTV(Ritonavir), IDV (Indinavir), SQV (Saquinavir), NFV (Nelfinavir), APV(Amprenavir), LPV (Lopinavir), fusion inhibitors such as T20, amongothers, fuseon and mixtures thereof, including anti-HIV compoundspresently in clinical trials or in development.

Other anti-HIV agents which may be used in coadministration withcompounds according to the present invention include, for example, otherNNRTI's (i.e., other than the NNRTI's according to the presentinvention) may be selected from the group consisting of nevirapine(BI-R6-587), delavirdine (U-90152S/T), efavirenz (DMP-266), UC-781(N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2methyl3-furancarbothiamide),etravirine (TMC 125), Trovirdine (Ly300046.HCl), MKC-442 (emivirine,coactinon), HI-236, HI-240, HI-280, HI-281, rilpivirine (TMC-278),MSC-127, HBY 097, DMP266, Baicalin (TJN-151) ADAM-II (Methyl3′,3′-dichloro-4′,4″-dimethoxy-5′,5″-bis(methoxycarbonyl)-6,6-diphenylhexenoate),Methyl3-Bromo-5-(1-5-bromo-4-methoxy-3-(methoxycarbonyl)phenyl)hept-1-enyl)-2-methoxybenzoate(Alkenyldiarylmethane analog, Adam analog),(5-chloro-3-(phenylsulfinyl)-2′-indolecarboxamide), AAP-BHAP (U-104489or PNU-104489), Capravirine (AG-1549, S-1153), atevirdine (U-87201E),aurin tricarboxylic acid (SD-095345),1-[(6-cyano-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine,1-[5-[[N-(methyl)methylsulfonylamino]-2-indolylcarbonyl-4-[3-(isopropylamino)-2-pyridinyl]piperazine,1-[3-(Ethylamino)-2-[pyridinyl]-4-[(5-hydroxy-2-indolyl)carbonyl]piperazine,1-[(6-Formyl-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine,1-[[5-(Methylsulfonyloxy)-2-indoyly)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine,U88204E, Bis(2-nitrophenyl)sulfone (NSC 633001), Calanolide A(NSC675451), Calanolide B,6-Benzyl-5-methyl-2-(cyclohexyloxy)pyrimidin-4-one (DABO-546), DPC 961,E-EBU, E-EBU-dm, E-EPSeU, E-EPU, Foscarnet (Foscavir), HEPT(1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine), HEPT-M(1-[(2-Hydroxyethoxy)methyl]-6-(3-methylphenyl)thio)thymine), HEPT-S(1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)-2-thiothymine), InophyllumP, L-737,126, Michellamine A (NSC650898), Michellamine B (NSC649324),Michellamine F,6-(3,5-Dimethylbenzyl)-1-[(2-hydroxyethoxy)methyl]-5-isopropyluracil,6-(3,5-Dimethylbenzyl)-1-(ethyoxymethyl)-5-isopropyluracil, NPPS, E-BPTU(NSC 648400), Oltipraz(4-Methyl-5-(pyrazinyl)-3H-1,2-dithiole-3-thione),N-{2-(2-Chloro-6-fluorophenethyl]-N′-(2-thiazolyl)thiourea (PETT Cl, Fderivative),N-{2-(2,6-Difluorophenethyl]-N′-[2-(5-bromopyridyl)]thiourea {PETTderivative),N-{2-(2,6-Difluorophenethyl]-N′-[2-(5-methylpyridyl)]thiourea {PETTPyridyl derivative),N-[2-(3-Fluorofuranyl)ethyl]-N′-[2-(5-chloropyridyl)]thiourea,N-[2-(2-Fluoro-6-ethoxyphenethyl)]-N′-[2-(5-bromopyridyl)]thiourea,N-(2-Phenethyl)-N′-(2-thiazolyl)thiourea (LY-73497), L-697,639,L-697,593, L-697,661,3-[2-(4,7-Difluorobenzoxazol-2-yl)ethyl}-5-ethyl-6-methyl(pypridin-2(1H)-thione(2-Pyridinone Derivative),3-[[(2-Methoxy-5,6-dimethyl-3-pyridyl)methyl]amine]-5-ethyl-6-methyl(pypridin-2(1H)-thione,R82150, R82913, R87232, R88703, R89439 (Loviride), R90385, S-2720,Suramin Sodium, TBZ (Thiazolobenzimidazole, NSC 625487),Thiazoloisoindol-5-one,(+)(R)-9b-(3,5-Dimethylphenyl-2,3-dihydrothiazolo[2,3-a]isoindol-5(9bH)-one,Tivirapine (R86183), UC-38 and UC-84, among others.

The term “pharmaceutically acceptable salt” is used throughout thespecification to describe, where applicable, a salt form of one or moreof the compounds described herein which are presented to increase thesolubility of the compound in the gastic juices of the patient'sgastrointestinal tract in order to promote dissolution and thebioavailability of the compounds. Pharmaceutically acceptable saltsinclude those derived from pharmaceutically acceptable inorganic ororganic bases and acids, where applicable. Suitable salts include thosederived from alkali metals such as potassium and sodium, alkaline earthmetals such as calcium, magnesium and ammonium salts, among numerousother acids and bases well known in the pharmaceutical art. Sodium andpotassium salts are particularly preferred as neutralization salts ofthe phosphates according to the present invention.

The term “pharmaceutically acceptable derivative” is used throughout thespecification to describe any pharmaceutically acceptable prodrug form(such as an ester, amide other prodrug group), which, uponadministration to a patient, provides directly or indirectly the presentcompound or an active metabolite of the present compound.

EXAMPLES

The following structures are ligands for BET (bromodomain and extraterminal domain). These ligands are used as an example only todemonstrate the current invention of using MDM2 E3 ligase to degrade atarget protein and in no way limit the present invention. In theexampled structures below, the target protein is BRD2 (BRD2, BRD3 andBRD4). In a certain embodiment, the PTM is selected from the groupconsisting of:

wherein “*” indicates one of the positions to connect linker.

The following are examples of androgen receptor ligands. These ligandsare used as examples only to demonstrate the current invention of usingMDM2 E3 ligase to degrade a target protein and in no way limit thepresent invention. In a particular embodiment, the PTM is selected fromthe group consisting of:

wherein “*” indicates one of the positions to connect linker.

The following is an example of EZH2 ligand. The ligands is used as anexample only to demonstrate the current invention of using MDM2 E3ligase to degrade a target protein and in no way limit the presentinvention. In a particular embodiment, the PTM is selected from thegroup consisting of:

wherein “*” indicates one of the positions to connect linker.

The following is an example of JNK ligand. The ligands is used as anexample only to demonstrate the current invention of using MDM2 E3ligase to degrade a target protein and in no way limit the presentinvention. In a particular embodiment, the PTM is selected from thegroup consisting of:

wherein “*” indicates one of the positions to connect linker.

The following are examples of MDM2 ligand derived chimeric moleculesusing MDM2 E3 ligase to degrade BRDs and androgen receptor and in no waylimit the present invention. In an embodiment, the chimeric molecule isselected from the group consisting of:

The following are examples of MDM2 ligand derived chimeric moleculesusing VHL E3 ligase to degrade MDM2, which provides examples for Formula(B) as described herein. Thus, in certain embodiments, the descriptionprovides a bifunctional molecules selected from the group consisting of:

The following are examples of MDM2 ligand derived chimeric moleculesusing MDM2 E3 ligase to degrade androgen receptor. In an embodiment, thechimeric molecule is selected from the group consisting of:

The following are examples of MDM2 ligand derived chimeric moleculesusing MDM2 E3 ligase to degrade EZH2. Thus, in certain additionalembodiments, the description provides a bifunctional compound selectedfrom the group consisting of:

The following are examples of MDM2 ligand derived chimeric moleculesusing MDM2 E3 ligase to degrade JNK. Thus, in certain additionalembodiments, the description provides a bifunctional compound selectedfrom the group consisting of:

In certain aspects, the description provides a composition, e.g., apharmaceutical composition or therapeutic composition comprising aneffective amount of at least one compound as described or exemplifiedherein, and a pharmaceutically acceptable excipient.

Synthetic Procedures

Compounds claimed in this document can be synthesized using syntheticmethods known in the art of organic chemistry. The following examplesare representatives of claimed compounds. All MDM2 ligand-derivedPROTACs disclosed in this document were analyzed for purity by LC/MS andall final compounds had purity larger than 95%.

Example 1 Synthesis of A1876

Step 1: Synthesis of tert-butylN-(14-[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0̂[2,6]]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido]-3,6,9,12-tetraoxatetradecan-1-yl)carbamate

Into a 100-mL round-bottom flask, was placed2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0̂[2,6]]trideca-2(6),4,7,10,12-pentaen-9-yl]aceticacid (70.0 mg, 0.17 mmol, 1.00 equiv, prepared from the correspondingcarboxylic acid tert-butyl ester as described in the literature: Chem. &Bio. 2015, 22, 755-763; PNAS 2016, June 6), tert-butylN-(14-amino-3,6,9,12-tetraoxatetradecan-1-yl)carbamate (59.0 mg, 0.18mmol, 1.00 equiv), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (80.0 mg, 0.21 mmol, 1.20 equiv),N,N-Diisopropylethylamine (0.1 mL, 3.00 equiv), N,N-dimethylformamide(1.0 mL). The resulting solution was stirred for 1.0 h at roomtemperature and diluted with water (20 mL). The mixture was extractedwith ethyl acetate (3×10 mL) and the organic layers were combined. Theresidue was applied onto a silica gel column and eluted withdichloromethane/methanol (10/1). This resulted in 160 mg (crude) oftert-butylN-(14-[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0̂[2,6]]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido]-3,6,9,12-tetraoxatetradecan-1-yl)carbamateas a colorless oil.

Step 2: Synthesis ofN-(14-amino-3,6,9,12-tetraoxatetradecan-1-yl)-2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0̂[2,6]]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamideInto a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed tert-butylN-(14-[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0̂[2,6]]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido]-3,6,9,12-tetraoxatetradecan-1-yl)carbamate(160 mg, 0.22 mmol, 1.00 equiv), hydrogen chloride/dioxane (10.0 mL).The resulting solution was stirred for 1 h at room temperature. Theresulting mixture was concentrated under vacuum. This resulted in 150.0mg (crude) ofN-(14-amino-3,6,9,12-tetraoxatetradecan-1-yl)-2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0̂[2,6]]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamideas a white solid.

Step 3:3-(3-Chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-{4-[(14-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0^(2,6)]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}-3,6,9,12-tetraoxatetradecan-1-yl)carbamoyl]-2-methoxyphenyl}-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide(A1876)

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placedN-(14-amino-3,6,9,12-tetraoxatetradecan-1-yl)-2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0̂[2,6]]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide(93.0 mg, 0.15 mmol, 1.00 equiv), racemate of4-[(2S,3R,4S,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-amido]-3-methoxybenzoicacid (80.0 mg, 0.13 mmol, 1.00 equiv, prepared according to literatureprocedure, J. Med. Chem. 2013, 56, 5979),O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (60.0 mg, 0.16 mmol, 1.20 equiv),N,N-Diisopropylethylamine (0.5 mL, 3.00 equiv), N,N-dimethylformamide(3.0 mL). The resulting solution was stirred for 1.0 h at roomtemperature and diluted with water (20 mL). The mixture was extractedwith ethyl acetate (3×10 mL) and the organic layers were combined. Thecrude product was purified by Prep-HPLC (mobile phase:water (10 mmol/LNH₄HCO₃) and CH₃CN, 6 min, UV detector at 220 nm), which resulted in10.7 mg (6%) of A1876 as a white solid.

¹H NMR (300 MHz, CD₃OD): δ8.35-8.20 (m, 1H), 7.80-7.70 (m, 1H),7.55-7.30 (m, 9H), 7.29-7.12 (m, 2H), 4.80-4.70 (m, 1H), 4.68-4.58 (m,2H), 4.18-3.99 (m, 1H), 3.88 (s, 3H), 3.71-3.54 (m, 18H), 3.52-3.40 (m,3H), 2.73 (s, 3H), 2.45 (s, 3H), 1.62-1.50 (m, 4H), 1.30-1.25 (m, 2H),0.98 (s, 9H); LC-MS calculated for C₆₀H₆₆C₁₃F₂N₉O₈S (m/z) 1216.38, obsd1216, 1218 [MH⁺, Cl³⁵ and Cl³⁷], t_(R)=2.49 (3.5 minute run).

Example 2 Preparation of A1893 and A1894

Preparation of (2R*,3S*,4R*,5S*)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-{4-[(14-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0^(2,6)]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}-3,6,9,12-tetraoxatetradecan-1-yl)carbamoyl]-2-methoxyphenyl}-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide(A1893) and(2S*,3R*,4S*,5R*)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-{4-[(14-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0^(2,6)]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}-3,6,9,12-tetraoxatetradecan-1-yl)carbamoyl]-2-methoxyphenyl}-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide(A1894)

A1876 was separated by preparative LC with a chiral column to providetwo fractions as A1893 and A1894.

Fraction 1: ¹H NMR (300 MHz, CD₃OD): δ8.35-8.27 (m, 1H), 7.80-7.70 (m,1H), 7.55-7.30 (m, 9H), 7.29-7.12 (m, 2H), 4.80-4.70 (m, 1H), 4.68-4.58(m, 2H), 4.18-3.99 (m, 1H), 3.88 (s, 3H), 3.71-3.54 (m, 18H), 3.52-3.40(m, 3H), 3.30-3.25 (m, 1H), 2.73 (s, 3H), 2.45 (s, 3H), 1.62-1.50 (m,4H), 1.30-1.25 (m, 1H), 0.98 (s, 9H); LC- calculated forC₆₀H₆₆C₁₃F₂N₉O₈S (m/z) 1216.38, obsd 1216, 1218 [MH⁺, Cl³⁵ and Cl³⁷],t_(R)=1.96 min (2.9 minute run).

Fraction 2: ¹H NMR (300 MHz, CD₃OD): δ8.35-8.27 (m, 1H), 7.80-7.70 (m,1H), 7.55-7.30 (m, 9H), 7.29-7.12 (m, 2H), 4.80-4.70 (m, 1H), 4.68-4.58(m, 2H), 4.18-3.99 (m, 1H), 3.88 (s, 3H), 3.71-3.54 (m, 18H), 3.52-3.40(m, 3H), 2.73-2.60 (m, 4H), 2.45 (s, 3H), 1.62-1.50 (m, 4H), 1.30-1.25(m, 1H), 0.98 (s, 9H); LC-MS calculated for C₆₀H₆₆C₁₃F₂N₉O₈S (m/z)1216.38, obsd 1216, 1218 [MH⁺, Cl³⁵ and Cl³⁷], t_(R)=1.96 min (2.9minute run).

Using the same synthetic method as described for A1876, A1893 and A1894,the following molecules were prepared: A1283, A1306, A1307, A1863,A1864, A1865, A1829, A1874, A1875, A1890, A1891 and a1892. The MDM2ligand for A1283, A1306 and A1306 was synthesized according toliterature procedure (J. Med. Chem. 2013, 56, 5979)

Example 3 Preparation of A1895

Step 1: Synthesis of 4-(4-methyl-1,3-thiazol-5-yl)benzonitrile

To a stirred solution of 4-bromobenzonitrile (20 g, 109.88 mmol) in DMA(250 mL) under a nitrogen atmosphere was added 4-methyl-1,3-thiazole(21.88 g, 220.67 mmol), palladium (II) acetate (743 mg, 3.31 mmol) andpotassium acetate (21.66 g, 220.71 mmol) at rt. The resulting solutionwas heated to 150° C. and stirred at this temperature for 5 h, at whichtime LC-MS indicated completion of reaction. The reaction was cooled tort, diluted with 1 L of water and extracted with ethyl acetate (300mL×3). The organic layers were combined, washed with saturated aqueoussolution of sodium chloride (200 mL), dried over anhydrous sodiumsulfate and then concentrated under reduced pressure to give a cruderesidue, which was purified by flash silica gel chromatography (eluent:ethyl acetate/petroleum ether, v:v=1:5) to give the titled compound(yield: 91%) as a white solid.

Step 2: Synthesis of [4-(4-methyl-1,3-thiazol-5-yl)phenyl]methanamine

To a stirred solution of 4-(4-methyl-1,3-thiazol-5-yl)benzonitrile (35g, 174.77 mmol) in tetrahydrofuran (1000 mL) was added LiAlH₄ (20 g,526.32 mmol) in portions at 0° C. in 10 min under a nitrogen atmosphere.The resulting solution was then stirred at 60° C. for 3 h, at which timeLC-MS indicated completion of reaction. The reaction was cooled to 0°C., then quenched by the addition water (20 mL, added slowly), aq.solution of NaOH (15%, 20 mL) and water (60 mL). The resulting mixturewas then extracted with ethyl acetate (300 mL×2). The organic layerswere combined, washed with saturated aqueous solution of sodium chloride(100 mL), dried over anhydrous sodium sulfate and then concentratedunder reduced pressure to give a crude residue, which was purified byflash silica gel chromatography (eluent: dichloromethane/methanol(v:v=10:1)) to give the titled compound (yield: 56%) as a yellow oil.

Step 3: Synthesis of tert-butyl(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidine-1-carboxylate

To a stirred solution of(2S,4R)-1-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid(2.7 g, 11.68 mmol) in N,N-dimethylformamide (20 mL) was added DIEA(2.52 g, 19.50 mmol), HATU (4.47 g, 11.76 mmol) and[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methanamine (2 g, 9.79 mmol) at rt.The resulting mixture was stirred at rt overnight, at which time LC-MSindicated completion of reaction. The reaction mixture was diluted by 20mL of water and extracted with ethyl acetate (50 mL×3). The organiclayers were combined, washed with saturated aqueous solution of sodiumchloride (50 mL), dried over anhydrous sodium sulfate and thenconcentrated under reduced pressure to give a crude residue, which waspurified by flash silica gel chromatography (eluent:dichloromethane/methanol (v:v=20:1)) to give the titled compound (yield:56%) as a yellow solid.

Step 4: Synthesis of(2S,4R)-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamidehydrochloride

To a solution of tert-butyl(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidine-1-carboxylate(45 g, 107.78 mmol) in dioxane was added a solution of hydrogen chloride(13.44 L) in dioxane (300 mL). The resulting solution was stirred for 2h at 20° C. The solids were collected by filtration to give the titledproduct (yield: 98%) as a yellow solid.

Step 5: Synthesis of tert-butylN-[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbama

To a stirred solution of(2S)-2-[[(tert-butoxy)carbonyl]amino]-3,3-dimethylbutanoic acid (15.73g, 68.01 mmol) in N,N-dimethylformamide (500 mL) was added DIEA (29.2 g,225.94 mmol), HATU (25.9 g, 68.12 mmol, 1.20 equiv) and(2S,4R)-2-amino-5-chloro-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pentanamide(20 g, 56.52 mmol) at rt. The resulting solution was stirred at rt for16 h, at which time LC-MS indicated completion of reaction. The reactionmixture was diluted by water (200 mL) and extracted with ethyl acetate(200 mL×3). The organic layers were combined, washed with saturatedaqueous solution of sodium chloride (50 mL×2), dried over anhydroussodium sulfate and then concentrated under reduced pressure to give acrude residue, which was purified by flash silica gel chromatography(eluent: ethyl acetate/petroleum ether (v:v=2:1)) to give the titledcompound (yield: 51%) as a yellow solid.

Step 6: Synthesis of (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamidehydrochloride

To a stirred solution of tert-butylN-[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate(12 g, 22.61 mmol) in dioxane (20 mL) was added a solution of hydrogenchloride (3.584 L) in dioxane (80 mL) at rt. The resulting solution wasstirred at rt for 2 h, at which time LC-MS indicated completion ofreaction. Precipitated solids were collected by filtration to give thetitled product (yield: 48%) as a yellow solid. ¹HNMR (400 MHz, CD₃OD): δ9.84-9.82 (s, 1H), 7.58-7.54 (m, 4H), 4.71-4.41 (m, 4H), 4.13-4.08 (m,1H), 3.86-3.71 (m, 2H), 3.36 (s, 1H), 2.60-2.58 (s, 3H), 2.35-2.07 (m,2H), 1.19-1.12 (m, 9H). LC-MS (ES⁺): m/z 431.11 [MH⁺], t_(R)=0.73 min.

Step 7: Synthesis of tert-butylN-(2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl)carbamate

Into a 100-mL round-bottom flask, was placed a solution of2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethan-1-ol (3.0 g, 15.52 mmol, 1.00equiv) in tetrahydrofuran/water (30/30 mL), di-tert-butyl dicarbonate(3.6 g, 16.49 mmol, 1.05 equiv), sodium hydroxide (2.5 g, 62.50 mmol,4.00 equiv). The resulting solution was stirred for 16 h at roomtemperature. The resulting solution was diluted with water (20 mL) andextracted with ethyl acetate (20 mL×3). The combined organic layers werewashed with brine (20 mL×1), dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with ethyl acetate/petroleum ether (1:1). Thisresulted in 2.0 g (44%) of tert-butylN-(2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl)carbamate as lightyellow oil. LC-MS (ES⁺): m/z 294.05 [MH⁺], t_(R)=0.93 min, (1.9 minuterun).

Step 8: Synthesis of14-[[(tert-butoxy)carbonyl]amino]-3,6,9,12-tetraoxatetradecanoic acid

Into a 50-mL round-bottom flask, was placed a solution of tert-butylN-(2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl)carbamate (300.0 mg,1.02 mmol, 1.00 equiv) in tetrahydrofuran (10 mL), sodium hydride (50.0mg, 2.08 mmol, 1.20 equiv), 2-bromoacetic acid (141.0 mg, 1.01 mmol,1.00 equiv). The resulting solution was stirred for 4 h at roomtemperature. The reaction was then quenched by the addition of water (20mL). The resulting solution was extracted with ethyl acetate (20 mL×3).The combined organic layers were washed with brine (20 mL×1). Theresulting mixture was concentrated under vacuum. This resulted in 310.0mg (86%) of14-[[(tert-butoxy)carbonyl]amino]-3,6,9,12-tetraoxatetradecanoic acid aslight yellow oil.

Step 9: Synthesis of tert-butylN-(1-[[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]-2,5,8,11-tetraoxatridecan-13-yl)carbamate

Into a 25-mL round-bottom flask, was placed a solution of14-[[(tert-butoxy)carbonyl]amino]-3,6,9,12-tetraoxatetradecanoic acid(175.0 mg, 0.50 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL),(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (250.0 mg, 0.54 mmol, 1.10equiv, from Step 6),O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (277.0 mg, 0.73 mmol, 1.20 equiv),N,N-diisopropylethylamine (0.5 mL, 5.00 equiv). The resulting solutionwas stirred for 2 h at room temperature. The reaction was then quenchedby the addition of water (20 mL). The resulting solution was extractedwith ethyl acetate (20 mL×3). The combined organic layers were washedwith brine (20 mL×1). The mixture was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was applied onto asilica gel column eluted with dichloromethane/methanol (10:1). Thisresulted in 227.0 mg (60%) of tert-butylN-(1-[[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]-2,5,8,11-tetraoxatridecan-13-yl)carbamateas yellow oil. LC-MS (ES⁺): m/z 764.35 [MH⁺], t_(R)=1.08 min, (1.9minute run).

Step 10: Synthesis of(2S,4R)-1-[(2S)-2-(14-amino-3,6,9,12-tetraoxatetradecanamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

Into a 25-mL round-bottom flask, was placed a solution of tert-butylN-(1-[[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]-2,5,8,11-tetraoxatridecan-13-yl)carbamate(227.0 mg, 0.30 mmol, 1.00 equiv) in dioxane (10 mL), then HCl (g) wasintroduced in. The resulting solution was stirred for 2 h at roomtemperature. The resulting mixture was concentrated under vacuum. Thisresulted in 190.0 mg (96%) of(2S,4R)-1-[(2S)-2-(14-amino-3,6,9,12-tetraoxatetradecanamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamideas yellow oil.

Step 11: Synthesis of3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[4-[(1-[[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]-2,5,8,11-tetraoxatridecan-13-yl)carbamoyl]-2-methoxyphenyl]pyrrolidine-2-carboxamide(A1895)

Into a 50-mL round-bottom flask, was placed a solution of racemate of4-[(2R, 3S, 4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-amido]-3-methoxybenzoicacid (80 mg, 0.13 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL),(2S,4R)-1-[(2S)-2-(14-amino-3,6,9,12-tetraoxatetradecanamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phen yl]methyl]pyrrolidine-2-carboxamide(320.0 mg, 0.48 mmol, 1.10 equiv),O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (64.0 mg, 0.17 mmol, 1.20 equiv),N,N-diisopropylethylamine (0.4 mL, 5.00 equiv). The resulting solutionwas stirred for 2 h at room temperature. The reaction was then quenchedby the addition of water (20 mL). The resulting solution was extractedwith ethyl acetate (20 mL×3) and the combined organic layers were washedwith brine (20 mL×1). The mixture was dried over anhydrous sodiumsulfate and concentrated under vacuum. The crude material was purifiedby prep-HPLC (column: XBridge Shield RP18 OBD Column, Sum, 19*150 mm;Mobile Phase A: water (10 mmol/L bicarbonate amine), Mobile Phase B:acetonitrile; Flow rate: 20 mL/min; Gradient: 50% B to 60% B in 9 min;254 nm). This resulted in 40.0 mg (24%) of (2R/2S, 3S/3R, 4R/4S,5S/SR)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[4-[(1-[[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl]-2,5,8,11-tetraoxatridecan-13-yl)carbamoyl]-2-methoxyphenyl]pyrrolidine-2-carboxamideas a white solid.

¹H NMR (300 MHz, CD₃OD) δ 8.84 (s, 1H), 8.34-8.31 (m, 1H), 7.62-7.64 (m,1H), 7.51 (s, 1H), 7.40-7.29 (m, 8H), 7.24-7.19 (m, 2H), 4.80-4.75 (m,1H), 4.70-4.55 (m, 3H), 4.55-4.45 (m, 1H), 4.27-4.25 (m, 1H), 4.10-4.00(m, 1H), 3.99-3.77 (m, 5H), 3.70-3.66 (m, 2H), 3.66-3.61 (m, 15H),3.59-3.55 (m, 2H), 2.48 (s, 3H), 2.25-2.19 (m, 1H), 2.19-1.92 (m, 1H),1.66-1.63 (m, 1H), 1.40-1.35 (m, 1H), 0.99 (s, 18H). LC-MS calcd forC₆₃H₇₆Cl₂F₂N₈O₁₁S (m/z) 1260.47, obsd 1284.05/1286.05 [M+Na⁺],t_(R)=2.27 min, (3.6 minute run).

Example 4 Preparation of A1896 and a1897

Preparation of (2R*,3S*,4R*,5S*)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-{4-[(1-{[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}-2,5,8,11-tetraoxatridecan-13-yl)carbamoyl]-2-methoxyphenyl}pyrrolidine-2-carboxamide(A1896) and(2S*,3R*,4S*,5R*)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-{4-[(1-{[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}-2,5,8,11-tetraoxatridecan-13-yl)carbamoyl]-2-methoxyphenyl}pyrrolidine-2-carboxamide(A1897)

A1895 was separated by Prep-chiral-HPLC (column: Phenomenex Lux 5uCellulose-4, AXIA Packed 250*21.2 mm, Sum; Mobile Phase: methanol inwater, Flow rate: 20 mL/min; run time: 24 min; 254/220 nm). Twofractions were collected. Fraction A (RT1: 11.68 min) gave A1896 (15 mg)as a white solid.

¹H NMR (300 MHz, CD₃OD) δ 8.83 (s, 1H), 8.34-8.31 (m, 1H), 7.62-7.64 (m,1H), 7.51 (s, 1H), 7.40-7.29 (m, 8H), 7.24-7.19 (m, 2H), 4.80-4.74 (m,3H), 4.70-4.55 (m, 3H), 4.33-4.28 (m, 1H), 4.06-4.03 (m, 1H), 3.98-3.94(m, 5H), 3.81-3.77 (m, 2H), 3.66-3.61 (m, 16H), 2.48 (s, 3H), 2.25-2.19(m, 1H), 2.19-1.92 (m, 1H), 1.66-1.63 (m, 1H), 1.40-1.35 (m, 1H), 0.99(s, 18H). LC-MS calcd for C₆₃H₇₆Cl₂F₂N₈O₁₁S (m/z) 1260.47, obsd1284.05/1286.05 [M+Na⁺], t_(R)=2.27 min, (3.6 minute run).

Fraction B (RT2: 20.22 min) gave A1897 also as a white solid (15 mg).

¹H NMR (300 MHz, CD₃OD) δ 8.83 (s, 1H), 8.34-8.31 (m, 1H), 7.62-7.64 (m,1H), 7.51 (s, 1H), 7.40-7.29 (m, 8H), 7.24-7.19 (m, 2H), 4.80-4.55 (m,6H), 4.33-4.28 (m, 1H), 4.06-4.03 (m, 1H), 3.98-3.94 (m, 5H), 3.81-3.77(m, 2H), 3.66-3.61 (m, 16H), 2.48 (s, 3H), 2.25-2.19 (m, 1H), 2.19-1.92(m, 1H), 1.72-1.63 (m, 1H), 1.40-1.25 (m, 1H), 1.02 (s, 18H). LC-MScalcd for C₆₃H₇₆Cl₂F₂N₈O₁₁S (m/z) 1260.47, obsd 1284.05/1286.05 [M+Na⁺],t_(R)=2.42 min, (3.6 minute run).

Using the same synthetic method as described for A1895, A1896 and A1897,the following molecules were prepared: A1877, A1907, A1908, A1909,A1910, and A1911.

Example 5 Preparation of A1717

Step 1: Synthesis of tert-butylN-[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamate

Into a 100-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of tert-butylN-[(1,3-trans)-3-hydroxy-2,2,4,4-tetramethylcyclobutyl]carbamate (600.0mg, 2.47 mmol, 1.00 equiv) in N,N-dimethylformamide (10.0 mL). This wasfollowed by the addition of sodium hydride (198.0 mg, 8.25 mmol, 2.00equiv), in portions at 0° C. After 30 min, to this was added2-chloro-4-fluorobenzonitrile (459.0 mg, 2.95 mmol, 1.20 equiv). Theresulting solution was stirred for 1 h at 70° C. The reaction mixturewas cooled to room temperature with a water bath. The reaction was thenquenched by the addition of water (20 mL). The resulting solution wasextracted with ethyl acetate (20 mL×3) and the organic layers werecombined. The resulting solution was washed with brine and concentrated.The residue was applied onto a silica gel column eluted with ethylacetate/petroleum ether (1/5). This resulted in 100.0 mg (11%) oftert-butylN-[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamateas colorless oil. LC-MS (ES⁺): m/z 279.10 [MH-100]⁺, t_(R)=1.20 min (2.5minute run).

Step 2: Synthesis of2-chloro-4-[(1,3-trans)-3-amino-2,2,4,4-tetramethylcyclobutoxy]-benzonitrile

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed tert-butylN-[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamate(500.0 mg, 1.32 mmol, 1.00 equiv), hydrogen chloride/dioxane (3 mL, 4M),1,4-dioxane (3 mL). The resulting solution was stirred for 1 h at roomtemperature. The resulting mixture was concentrated under vacuum. Thisresulted in 447 mg (87%) of2-chloro-4-[(1,3-trans)-3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrileas a white solid.

Step 3: Synthesis of4-[[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl]phenylacetate

Into a 25-mL round-bottom flask, was placed a solution of4-(acetyloxy)benzoic acid (100.0 mg, 0.56 mmol, 1.00 equiv) inN,N-dimethylformamide (10 mL),2-chloro-4-[(1,3-trans)-3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile(190.0 mg, 0.68 mmol, 1.10 equiv), HATU (253.0 g, 665.39 mmol, 1.20equiv), DIEA (0.5 mL, 5.00 equiv). The resulting solution was stirredfor 2 h at room temperature. The reaction was then quenched by theaddition of water (10 mL). The resulting solution was extracted withethyl acetate (10 mL×3) and the organic layers were combined. Theresulting mixture was washed with brine (10 mL×1). The mixture was driedover anhydrous sodium sulfate and concentrated under vacuum. Thisresulted in 230.0 mg (94%) of4-[[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl]phenylacetate as a light brown solid. LC-MS (ES⁺): m/z 441.00 [M+H⁺],t_(R)=1.09 min

Step 4: Synthesis of4-hydroxy-N-[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide

Into a 50-mL round-bottom flask, was placed4-[[(R1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl]phenylacetate (230.0 mg, 0.52 mmol, 1.00 equiv), sodium hydroxide (100.0 mg,2.50 mmol, 3.00 equiv) and methanol (10 mL). The resulting solution wasstirred at room temperature. The resulting mixture was concentratedunder vacuum and diluted with water (10 mL). The pH value of thesolution was adjusted to 4-5 with hydrogen chloride (1 mol/L). Theresulting solution was extracted with ethyl acetate (10 mL×3) and theorganic layers were combined. The solution was washed with brine (10mL×1) and concentrated under vacuum. The residue was applied onto asilica gel column eluted with ethyl acetate/petroleum ether (1:1). Thisresulted in 200.0 mg (96%) of4-hydroxy-N-[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]-benzamideas light yellow oil.

Step 5: Synthesis of 2-[2-(benzyloxy)ethoxy]ethyl4-methylbenzene-1-sulfonate

Into a 250-mL round-bottom flask, 2-[2-(benzyloxy)ethoxy]ethan-1-ol (3.0g, 15.29 mmol, 1.00 equiv), 4-methylbenzene-1-sulfonyl chloride (4.36 g,22.87 mmol, 1.50 equiv), triethylamine (3.09 g, 30.54 mmol, 2.00 equiv),4-dimethylaminopyridine (933.0 mg, 7.64 mmol, 0.50 equiv) were mixed indichloromethane (20 mL). The resulting solution was stirred for 3 h atroom temperature. The mixture was applied onto a silica gel columneluted with ethyl acetate/petroleum ether (1/3). This resulted in 4.9 g(91%) of 2-[2-(benzyloxy)ethoxy]ethyl 4-methylbenzene-1-sulfonate aslight yellow oil.

Step 6: Synthesis of tert-butylN-(1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl)carbamate

Into a 25-mL round-bottom flask, sodium hydride (67 mg, 2.79 mmol, 1.20equiv, 60% in oil) was added to a solution of tert-butylN-2-[2-(2-hydroxyethoxy)ethoxy]ethylcarbamate (320.0 mg, 1.28 mmol, 1.00equiv) in N,N-dimethylformamide (10 mL) at 0° C. The mixture was stirredfor 15 min at that temperature. Then 2-[2-(benzyloxy)ethoxy]ethyl4-methylbenzene-1-sulfonate (536 mg, 1.53 mmol, 1.20 equiv) was addedand the reaction was warmed to room temperature and stirred for 4 h.After quenched by addition of water, the resulting solution wasextracted with ethyl acetate (50 mL×3) and the organic layers werecombined. The resulting mixture was washed with brine (50 mL×3) anddried over anhydrous sodium sulfate. The filtered solution wasconcentrated and the residue was applied onto a silica gel column elutedwith ethyl acetate/petroleum ether (4/1). This resulted in 290 mg (53%)of tert-butyl N-(1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl)carbamateas light yellow oil. LC-MS (ES⁺): m/z 428.95 [M+H⁺], t_(R)=0.92 min,(1.9 minute run).

Step 7: Synthesis of tert-butyl14-hydroxy-3,6,9,12-tetraoxatetradecylcarbamate

Into a 50-mL round-bottom flask, palladium on carbon (200.0 mg) wasadded to a solution of tert-butylN-(1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl)carbamate (290.0 mg,0.68 mmol, 1.00 equiv) in methanol (10 mL) at room temperature undernitrogen atmosphere. The reaction flask was vacuumed and charged with ahydrogen balloon. The resulting solution was stirred for 8 h at 40° C.in an oil bath. The reaction mixture was then filtered through a Celitepad and the filtrate was concentrated under reduced pressure. Thisresulted in 220 mg (crude) of tert-butyl14-hydroxy-3,6,9,12-tetraoxatetradecylcarbamate as yellow oil

Step 8: Synthesis of tert-butylN-(14-[[(4-methylbenzene)sulfonyl]oxy]-3,6,9,12-tetraoxatetradecan-1-yl)carbamate

Into a 25-mL round-bottom flask, tert-butylN-(14-hydroxy-3,6,9,12-tetraoxatetradecan-1-yl)carbamate (228.0 mg, 0.68mmol, 1.00 equiv), 4-methylbenzene-1-sulfonyl chloride (192.0 mg, 1.01mmol, 1.50 equiv), triethylamine (136.2 mg, 1.35 mmol, 2.00 equiv),4-dimethylaminopyridine (16.4 mg, 0.13 mmol, 0.20 equiv) were mixed indichloromethane (10 mL). The resulting solution was stirred for 8 h atroom temperature. The residue was applied onto a silica gel columneluted with ethyl acetate/petroleum ether (3/2). This resulted in 110.0mg (33%) of tert-butylN-(14-[[(4-methylbenzene)sulfonyl]oxy]-3,6,9,12-tetraoxatetradecan-1-yl)carbamateas light yellow oil. LC-MS (ES⁺): m/z 492.00 [M+H⁺], t_(R)=0.93 min,(1.9 minute run).

Step 9: Synthesis of tert-butylN-[1-(4-[[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl]phenyl)-1,4,7,10,13-pentaoxapentadecan-15-yl]carbamate

Into a 25-mL round-bottom flask, was placed4-hydroxy-N-[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide(50.0 mg, 0.13 mmol, 1.00 equiv), potassium carbonate (34.7 mg, 0.25mmol, 2.00 equiv), tert-butylN-(14-[(4-methylbenzene)sulfonyl]oxy-3,6,9,12-tetraoxatetradecan-1-yl)carbamate(74.0 mg, 0.15 mmol, 1.20 equiv) in N,N-dimethylformamide (5.0 mL). Theresulting solution was stirred for 5 h at 80° C. in an oil bath. Thereaction was quenched with 50 mL of water. The resulting solution wasextracted with ethyl acetate (50 mL×3) and the organic layers werecombined. The resulting mixture was washed with brine (50 mL×3) anddried over anhydrous sodium sulfate. After the evaporation of solvents,the crude product was purified by prep-TLC with ethyl acetate/petroleumether (4/1). This resulted in 110.0 mg of tert-butylN-[1-(4-[[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl]phenyl)-1,4,7,10,13-pentaoxapentadecan-15-yl]carbamateas light yellow oil. LC-MS (ES⁺): m/z 740.10/742.10 [M+Na⁺], t_(R)=1.14min, (1.9 minute run).

Step 10: Synthesis of4-[(14-amino-3,6,9,12-tetraoxatetradecan-1-yl)oxy]-N-[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamidehydrochloride

Into a 25-mL round-bottom flask, hydrogen chloride (2 mL, 2N in dioxane)was added to a solution of tert-butyl N-[1-(4-[[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl]phenyl)-1,4,7,10,13-pentaoxapentadecan-15-yl]carbamate(110.0 mg, 0.15 mmol, 1.00 equiv) in methanol (15 mL). The resultingsolution was stirred for 3 h at room temperature and concentrated undervacuum. This resulted in 100.0 mg (crude) of4-[(14-amino-3,6,9,12-tetraoxatetradecan-1-yl)oxy]-N-[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamidehydrochloride as light yellow oil.

Step 11: Synthesis of3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[1-(4-[[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl]phenyl)-1,4,7,10,13-pentaoxapentadecan-15-yl]pyrrolidine-2-carboxamide(A1717)

Into a 25-mL round-bottom flask, was placed(2R/2S,3S/3R,4R/4S,5S/5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxylicacid (59.4 mg, 0.13 mmol, 1.00 equiv, prepared according to literatureprocedure: J. Med. Chem. 2013, 56, 5979),4-[(14-amino-3,6,9,12-tetraoxatetradecan-1-yl)oxy]-N-[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamidehydrochloride (100.0 mg, 0.15 mmol, 1.20 equiv),N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophospate (58.0 mg, 0.15 mmol, 1.20 equiv),N,N-dimethylformamide (5.0 mL). N,N-Diisopropylethylamine (82.3 mg, 0.64mmol, 5.00 equiv) was added and the reaction was stirred for 2 h at roomtemperature. The reaction mixture was quenched by addition of 20 mL ofwater. The resulting solution was extracted with ethyl acetate (50 mL×3)and the organic layers were combined. The resulting mixture was washedwith brine (50 mL×3) and dried over anhydrous sodium sulfate. After theevaporation of solvents, the crude product was purified by Prep-HPLCwith the following conditions: Column, XBridge Shield RP18 OBD Column, 5um, 19*150 mm; mobile phase:water with 10 mmol/L ammonium bicarbonateand acetonitrile (hold 74.0% acetonitrile in 10 min); Detector, UV 254nm. This resulted in 45 mg (33%) of3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[1-(4-[[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl]phenyl)-1,4,7,10,13-pentaoxapentadecan-15-yl]pyrrolidine-2-carboxamide(A1717) as a white solid.

¹H NMR (400 MHz, CD₃OD): δ7.82-7.80 (d, J=8.0 Hz, 2H), 7.74-7.65 (m,2H), 7.39-7.31 (m, 3H), 7.26-7.22 (m, 2H), 7.14 (d, J=2.8 Hz, 1H),7.05-6.98 (m, 3H), 4.73-4.71 (d, J=7.2 Hz, 1H), 4.44-4.42 (d, J=8.4 Hz,1H), 4.29 (s, 1H), 4.23-4.20 (d, J=9.2 Hz, 2H), 4.16 (s, 1H), 4.00 (m,1H), 3.90-3.88 (d, J=9.2 Hz, 2H), 3.74-3.57 (m, 13H), 3.50-3.40 (m, 1H),3.36-3.32 (m, 1H), 1.65-1.55 (m, 1H), 1.31-1.29 (m, 1H), 1.28 (s, 6H),1.24 (s, 6H), 0.95 (s, 9H); LC-MS calcd for C₅₅H₆₄Cl₃F₂N₅O₈ (m/z)1067.48, obsd 1068.50 [M+H⁺], t_(R)=2.76 min, (3.6 minute run).

Example 6 Preparation of A1720 and A1735

Preparation of(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[1-(4-{[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenyl)-1,4,7,10,13-pentaoxapentadecan-15-yl]pyrrolidine-2-carboxamide(A1720) and(2S,3R,4S,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[1-(4-{[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenyl)-1,4,7,10,13-pentaoxapentadecan-15-yl]pyrrolidine-2-carboxamide(A1735)

A1717 was separated by preparative chiral HPLC (Column: Chiralpak IA2*25 cm, 5 um; Mobile Phase A: hexane; Mobile Phase B: ethanol; Flowrate: 15 mL/min; Gradient: 50 B to 50 B in 35 min; 254/220 nm). Thechiral separation resulted in two fractions. Fraction A (RT1: 16.962min) gave 10.0 mg (29%) of(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[1-(4-[[(1,3-tran)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl]phenyl)-1,4,7,10,13-pentaoxapentadecan-15-yl]pyrrolidine-2-carboxamideas a white solid.

¹H NMR (400 MHz, CD₃OD): δ 7.82-7.80 (d, J=8.0 Hz, 2H), 7.74-7.65 (m,2H), 7.39-7.31 (m, 3H), 7.26-7.22 (m, 2H), 7.14 (d, J=2.8 Hz, 1H),7.05-6.98 (m, 3H), 4.73-4.71 (d, J=7.2 Hz, 1H), 4.44-4.42 (d, J=8.4 Hz,1H), 4.29 (s, 1H), 4.23-4.20 (d, J=9.2 Hz, 2H), 4.16 (s, 1H), 4.00 (m,1H), 3.90-3.88 (d, J=9.2 Hz, 2H), 3.74-3.57 (m, 13H), 3.50-3.40 (m, 1H),3.36-3.32 (m, 1H), 1.65-1.55 (m, 1H), 1.31-1.29 (m, 1H), 1.28 (s, 6H),1.24 (s, 6H), 0.95 (s, 9H); LC-MS calcd for C₅₅H₆₄Cl₃F₂N₅O₈ (m/z)1067.48, obsd 1068.10/1070.10 [M+H⁺], t_(R)=2.62 min, (3.6 minute run).

The second fraction (RT2: 28.90 min) gave 10.0 mg (29%) of(2S,3R,4S,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[1-(4-[[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl]phenyl)-1,4,7,10,13-pentaoxapentadecan-15-yl]pyrrolidine-2-carboxamideas a white solid.

¹H NMR (400 MHz, CD₃OD): δ 7.82-7.80 (d, J=8.0 Hz, 2H), 7.74-7.65 (m,2H), 7.39-7.31 (m, 3H), 7.26-7.22 (m, 2H), 7.14 (d, J=2.8 Hz, 1H),7.05-6.98 (m, 3H), 4.73-4.71 (d, J=7.2 Hz, 1H), 4.44-4.42 (d, J=8.4 Hz,1H), 4.29 (s, 1H), 4.23-4.20 (d, J=9.2 Hz, 2H), 4.16 (s, 1H), 4.00 (m,1H), 3.90-3.88 (d, J=9.2 Hz, 2H), 3.74-3.57 (m, 13H), 3.50-3.40 (m, 1H),3.36-3.32 (m, 1H), 1.65-1.55 (m, 1H), 1.31-1.29 (m, 1H), 1.28 (s, 6H),1.24 (s, 6H), 0.95 (s, 9H); LC-MS calcd for C₅₅H₆₄Cl₃F₂N₅O₈ (m/z)1067.48, obsd 1068.10/1070.10 [M+H⁺], t_(R)=2.62 min, (3.6 minute run).

Compounds A1751, A1603, A1621 and A1688 were prepared using the samemethod as described for the preparation of A1717, A1720 and A1735

Example 7 Preparation of A2434

Step 1: Synthesis of 2-chloro-4-isothiocyanatobenzonitrile

To a stirred solution of 4-amino-2-chlorobenzonitrile (1 g, 6.55 mmol)in dichloromethane (9 mL) was added sodium bicarbonate (2.21 g, 26.31mmol) and water (9 mL), followed by addition of thiophosgene (817 mg,7.11 mmol) drop wise in 30 min at 0° C. The resulting mixture wasstirred for 1 h at room temperature. The reaction mixture was dilutedwith dichloromethane (200 mL), washed with brine (50 mL×2), dried overanhydrous sodium sulfate and then concentrated under reduced pressure togive a crude residue. The residue was purified by flash silica gelchromatography (eluent: ethyl acetate/petroleum ether (v:v=1:30)) togive the desired product (yield: 71%)¹HNMR (400 MHz, CDCl₃): δ 7.69 (d,J=8.0 Hz, 1H), 7.38 (s, 1H), 7.28 (m, 1H).

Step 2: Synthesis of 2-chloro-4-[3-(4-hydroxyphenyl)-5-imino-4,4-dimethyl-2-sulfanylideneimidazolidin-1-yl]benzonitrile

To a stirred solution of 2-chloro-4-isothiocyanatobenzonitrile (399 mg,2.05 mmol) in toluene (5 mL) was added2-[(4-hydroxyphenyl)amino]-2-methylpropanenitrile (300 mg, 1.70 mmol)and 4-dimethylaminopyridine (312 mg, 2.55 mmol). The resulting solutionwas then heated in an oil bath to 100° C. and stirred at the sametemperature for 16 h. The resulting mixture was concentrated undervacuum. The residue was purified by flash silica gel chromatography(eluent: ethyl acetate/petroleum ether, v:v=1:1) to give the desiredproduct (yield: 48%) as a brown solid. LC-MS (ES⁺): m/z 370.95 [M+H⁺],t_(R)=0.74 min.

Step 3: Synthesis of2-chloro-4-[3-(4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl]benzonitrile

To a stirred solution of 2-chloro-4-[3-(4-hydroxyphenyl)-5-imino-4,4-dimethyl-2-sulfanylideneimidazolidin-1-yl]benzonitrile (300 mg, 0.81mmol) in methanol (6 mL) was added aqueous hydrogen chloride (2N, 3.0mL). The resulting solution was then heated in an oil bath to 100° C.and stirred at the same temperature for 2 h. The reaction mixture wasdiluted with water (30 mL), extracted with ethyl acetate (60 mL×3),washed with water (50 mL), dried over anhydrous sodium sulfate andconcentrated under vacuum to give titled product (yield: 93%) as ayellow solid, which was used for next step without any furtherpurifications. LC-MS (ES⁺): m/z 372.00 [M+H⁺], t_(R)=0.97 min.

Step 4 and Step 5: Preparation of(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(3-{[5-(4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}phenoxy)pentyl]oxy}propyl)-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide(A2434)

Step 4 and step 5 were carried out using the method as described for thesynthesis of A1717.

Compound A2434 was isolated as a solid. LC-MS calcd for C₅₀H₅₁Cl₂F₅N₆O₄S(m/z) 997.94, obsd 997/999.

Compound A2435 was prepared with the same method as described for thepreparation of A2434.

In the case of the preparation of compound A679, A680 and A702, thesimilar synthetic route was used. The MDM2 ligand of imidazolinechemotype was synthesized according to literature procedure (ACS Med.Chem. Lett. 2103, 4, 466).

Example 8 Preparation of A2844

Step 1: Synthesis of 5-bromo-2-methyl-3-nitrobenzoic acid

To a stirred solution of 2-methyl-3-nitrobenzoic acid (10 g, 55 mmol) inconc. H₂SO₄ (40 mL), 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (9g, 32 mmol) was added portion wise at room temperature and reaction wasstirred at room temperature for 5 h. Then the reaction mass was pouredon an ice cold water. Solid was filtered, and the resulting residue waswashed with water and dried under vacuum to afford5-bromo-2-methyl-3-nitrobenzoic acid (12 g, 84%) as a light yellowsolid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.28 (d, J=2.0 Hz, 1H), 8.13 (d,J=2.0 Hz, 1H), 2.51 (s, 3H)

Step 2: Synthesis of methyl 5-bromo-2-methyl-3-nitrobenzoate

A mixture of 5-bromo-2-methyl-3-nitrobenzoic acid (12 g, 41 mmol) inSOCl₂/MeOH (v:v=1:10) (250 mL) was heated to reflux overnight. Thereaction mixture was cooled and concentrated. The residue was dissolvedin 300 mL of ethyl acetate. The organic layer was washed sequentiallywith sat. aq. NaHCO₃ and brine, dried over Na₂SO₄, and concentrated. Theresidue was purified by chromatography (silica gel, petroleumether/ethyl acetate (20:1, v:v)) to afford the desired compound (11 g,yield: 87%). ¹H NMR (400 MHz, CDCl₃): δ 8.12 (d, J=2.0 Hz, 1H), 7.97 (d,J=2.0 Hz, 1H), 3.95 (s, 3H), 2.57 (s, 3H)

Step 3: Synthesis of methyl 3-amino-5-bromo-2-methylbenzoate

To a stirred solution of methyl 5-bromo-2-methyl-3-nitrobenzoate (11 g,40 mmol) in ethanol (100 mL), was added NH₄Cl solution (13 g in 50 mLwater, 240 mmol) followed by Fe powder (20 g, 360 mmol). The resultingreaction was stirred at 80° C. for 2-3 h. Then the reaction mixture wasfiltered and the filtrate was concentrated till dryness to give a solidwhich was dissolved in sat. sodium bicarbonate solution. Aqueous layerwas extracted with ethyl acetate (3×100 mL). The combined organic layerswere dried over sodium sulfate and concentrated to afford the desiredcompound (8.1 g, 83%).

¹H NMR (400 MHz, CDCl₃): δ 7.33 (s, 1H), 6.94 (s, 1H), 3.87 (s, 3H),3.79 (br, 2H), 2.28 (s, 3H)

Step 4: Synthesis of methyl5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl) amino) benzoate

To a solution of methyl 3-amino-5-bromo-2-methylbenzoate (2 g, 8.2 mmol)in dichloromethane (20 mL) and acetic acid (2.5 g, 40 mol) was addedtetrahydropyran-4-one (1.2 g, mol 12 mmol) at 25° C. After 2.5 h,NaCNBH₃ was added into the reaction in portions and the mixture wasstirred overnight. The reaction was quenched with a solution of sodiumhydroxide (1.6 g, 40 mmol) in water (50 mL). After stirring for 10minutes at ambient temperature, the organic layer was washed with water(2×50 mL), dried (Na₂SO₄) and concentrated. The crude product waspurified by silica gel chromatography eluting with 5-20% ethyl acetatein petroleum to afford the desired compound (1.3 g, 50%) as a lightyellow oil. ¹H NMR 400 MHz, DMSO-d₆): δ 6.97 (s, 1H), 6.93 (s, 1H), 4.99(d, J=8.0 Hz, 1H), 3.87 (d, d, J=10.80 Hz, 2H), 3.80 (s, 3H), 3.60 (br,1H), 3.44 (t, J=11.6 Hz, 3H), 2.15 (s, 3H), 1.84 (d, J=12.4 Hz, 2H),1348-1.57 (m, 2H)

Step 5: Synthesis of methyl5-bromo-3-[ethyl(oxan-4-yl)amino]-2-methylbenzoate

To a stirred solution of methyl5-bromo-2-methyl-3-[(oxan-4-yl)amino]benzoate (1 g, 119 mmol) in THF (20mL) was added LiHDMS (1.0M, 2.0 eq, THF) at 0° C. After 30 min, EtI (4.0eq) was added into the mixture at 0° C. Then reaction mixture wasstirred at rt for 3 h. Saturated NaHCO₃ was added and the mixture wasseparated. The aqueous layer was extracted with CH₂Cl₂ and the combinedorganic layers were concentrated in vacuo to afford the desired product(1.2 g crude) which was used into next step without furtherpurification.

Step 6: Synthesis of5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoic acid

To a stirred solution of5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate (1.2g, crude) in ethanol (15 mL) was added LiOH (0.3 g, 10 mmol) and theresulting mixture was stirred at 60° C. for 1 h. Upon the completion ofthe reaction as determined by TLC, the solvent was removed under reducedpressure and the residue was acidified with 1N HCl until pH˜5, and itwas concentrated. The crude product was purified by silica gelchromatography eluting with 5-10% (CH₃OH/DCM) to afford the desiredproduct (0.7 g, 70%) as a light yellow oil. ¹H NMR (400 MHz, CDCl₃): δ7.88 (s, 1H), 7.42 (s, 1H), 3.98 (d, J=11.2 Hz, 2H), 3.34 (t, J=11.2 Hz,2H), 3.03-3.09 (m, 2H), 2.95-3.00 (m, 1H), 2.52 (s, 3H), 1.64-1.73 (m,4H), 0.88 (t, J=6.8 Hz, 3H)

Step 7: Synthesis of5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide

The acid from step 6 (0.5 g, 1.5 mmol) was dissolved in DMF (5 mL), and3-(amino methyl)-4,6-dimethylpyridin-2(1H)-one (0.45 g, 2.9 mmol) andDIEA (0.84 g, 5.8 mmol) were added. The reaction mixture was stirred atroom temperature for 15 minutes, and then PYBOP (1.6 g, 3.0 mmol) wasadded. The mixture was stirred at room temperature for 3 h. Upon thecompletion of the reaction as determined by TLC, the reaction mixturewas poured onto ice-cold water (150 mL). The mixture was stirred foranother 10 minutes and the solid was collected by filtration. The solidwas washed with water (50 mL) and dried by air. Then the solid wasslurried in 5% MeOH in DCM solution to afford desired product as a solid(200 mg, 30%). ¹H NMR (DMSO-d₆, 400 MHz) δ 11.46 (s, 1H), 8.21 (s, 1H),7.31 (s, 1H), 7.09 (s, 1H), 5.86 (s, 1H), 4.26 (d, J=4.4 Hz, 2H), 3.83(d, J=9.60 Hz, 2H), 3.20-3.27 (m, 2H), 3.00-3.02 (m, 3H), 2.19 (s, 3H),2.15 (s, 3H), 2.11 (s, 3H), 1.48-1.62 (m, 4H), 0.78 (t, J=6.8 Hz, 3H).

Step 8 to step 13: Synthesis of3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-[4-({1-[4-(3-{[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]carbamoyl}-5-[ethyl(oxan-4-yl)amino]-4-methylphenyl)phenyl]-1,4,7,10,13,16-hexaoxaoctadecan-18-yl}carbamoyl)-2-methoxyphenyl]-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide(A2844)

Reactions in step 8 through step 10 were carried out using the standardprocedure of tosylation on hydroxyl group, tosyl group displacement bybis-Boc-amine under potassium carbonate condition and tosyl groupdisplacement by phenol. The Suzuki coupling in Step 11 was carried outusing palladium tetrakis(triphenylphosphine) under the stand Suzukicoupling condition. The final two steps in forming A2844 were followedthe same procedure as described for the synthesis of A1717. CompoundA2844 was isolated as a solid.

¹H NMR (400 MHz, CD₃OD, ppm) δ 8.41-8.36 (m, 1H), 7.78-7.69 (m, 1H),7.59-7.46 (m, 4H), 7.45-7.33 (m, 4H), 7.32-7.22 (m, 3H), 7.02-6.97 (m,2H), 6.11 (s, 1H), 4.79-4.76 (m, 1H), 4.65-4.61 (m, 1H), 4.51 (s, 2H),4.18-4.13 (m, 2H), 4.11-4.05 (m, 1H), 3.99 (s, 3H), 3.98-3.88 (m, 2H),3.85-3.3.79 (m, 2H), 3.71-3.53 (m, 20H), 3.42-3.31 (m, 2H), 3.18-3.03(m, 3H), 2.40 (s, 3H), 2.32 (s, 3H), 2.25 (s, 3H), 1.79-1.62 (m, 5H),1.41-1.32 (m, 1H), 1.05 (s, 9H), 0.92-0.88 (t, J=6.8 Hz, 3H).

LC-MS calcd for C₇₂H₈₇Cl₂F₂N₇O₁₂ (m/z) 1351.40, obsd 1352.70 (M+H⁺);t_(R)=2.15 min (3.0 minute run).

Compound A2790 was prepared using the same method as described for thepreparation of A2844.

Example 9 Preparation of A2766

Step 1: Synthesis of[(2E)-3-(dimethylamino)-2-[2-(methylsulfanyl)pyrimidin-4-yl]prop-2-en-1-ylidene]dimethylazanium

Into a 100 mL 3-necked round-bottom flask, was placed a solution ofoxalyl dichloride (6.6 mL, 2.00 equiv) inchloroform/N,N-dimethylformamide (45/6 mL) at 0° C. The above mixturewas stirred for 30 min at 45° C. The reaction was cooled to 0° C.4-methyl-2-(methylsulfanyl)pyrimidine (5.0 g, 142.65 mmol, 1.00 equiv)was added to the solution separately at 0° C. The resulting solution wasstirred for 16 h at 45° C. in an oil bath. The solids were collected byfiltration. This resulted in 8.5 g (90%) of[(2E)-3-(dimethylamino)-2-[2-(methylsulfanyl)pyrimidin-4-yl]prop-2-en-1-ylidene]-dimethylazaniumas a yellow solid.

LC-MS (ES⁺): m/z 250.95 [M+H⁺], t_(R)=0.38 min, (1.9 minute run).

Step 2: Synthesis of 2-(methylsulfanyl)-4-(1,2-oxazol-4-yl)pyrimidine

Into a 1000 mL 3-necked round-bottom flask, was placed a solution ofhydroxylamine hydrogen chloride (6.4 g, 92.75 mmol, 3.00 equiv) in water(300 mL), sodium carbonate (14.3 g, 134.92 mmol, 4.40 equiv),[(2E)-3-(dimethylamino)-2-[2-(methylsulfanyl)pyrimidin-4-yl]prop-2-en-1-ylidene]dimethylazanium(7.7 g, 30.63 mmol, 1.00 equiv). The resulting solution was stirred for5 h at room temperature. The solids were collected by filtration,concentrated under vacuum. This resulted in 2.9 g (49%) of2-(methylsulfanyl)-4-(1,2-oxazol-4-yl)pyrimidine as a brown solid.

LC-MS (ES⁺): m/z 193.95[MH⁺], t_(R)=1.22 min, (2.6 minute run).

Step 3: Synthesis of2-[2-(methylsulfanyl)pyrimidin-4-yl]-3-oxopropanenitrile

Into a 25-mL round-bottom flask, was placed a solution of2-(methylsulfanyl)-4-(1,2-oxazol-4-yl)pyrimidine (1.0 g, 5.18 mmol, 1.00equiv) in methanol/water (5/5 mL). Sodium hydroxide (210.0 mg, 5.25mmol, 1.00 equiv) was added. The resulting solution was stirredovernight at 70° C. in an oil bath. The resulting mixture wasconcentrated under vacuum. The pH value of the solution was adjusted to3-4 with hydrogen chloride. The solids were collected by filtration,concentrated under vacuum. This resulted in 1.0 g (100%) of2-[2-(methylsulfanyl)pyrimidin-4-yl]-3-oxopropanenitrile as a brownsolid.

LC-MS (ES⁺): m/z 193.85[MH⁺], t_(R)=0.48 min, (1.9 minute run).

Step 4: Synthesis of1-benzyl-4-[2-(methylsulfanyl)pyrimidin-4-yl]-1H-pyrazol-5-amine

Into a 100-mL round-bottom flask, was placed a solution of2-[2-(methylsulfanyl)pyrimidin-4-yl]-3-oxopropanenitrile (1.0 g, 5.18mmol, 1.00 equiv) in ethanol/3M hydrogen chloride (10/6 mL).Benzylhydrazine hydrogen chloride (1.5 g, 7.73 mmol, 1.50 equiv) wasadded. The resulting solution was stirred for 2 h at 83° C. in an oilbath. The resulting mixture was concentrated under vacuum. The pH valueof the solution was adjusted to 9 with sodium carbonate. The resultingsolution was extracted with dichloromethane (20 mL×3) and the organiclayers were combined and concentrated under vacuum. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(1:1). This resulted in 900.0 mg (58%) of1-benzyl-4-[2-(methylsulfanyl)pyrimidin-4-yl]-1H-pyrazol-5-amine as agolden solid. LC-MS (ES⁺): m/z 297.90[MH⁺], t_(R)=0.83 min, (1.9 minuterun).

Step 5: Synthesis of1-benzyl-N,N-dimethyl-4-[2-(methylsulfanyl)pyrimidin-4-yl]-1H-pyrazol-5-amine

Into a 25-mL round-bottom flask, was placed a solution of1-benzyl-4-[2-(methylsulfanyl)pyrimidin-4-yl]-1H-pyrazol-5-amine (150.0mg, 0.50 mmol, 1.00 equiv) in tetrahydrofuran (10 mL), sodium hydride(61.0 mg, 2.54 mmol, 3.00 equiv) was added to the solution separately at0° C., 30 min later. To this mixture iodomethane (0.4 mL, 10.00 equiv)was added. The resulting solution was stirred for 12 h at roomtemperature. The reaction was then quenched by the addition of water (20mL). The resulting solution was extracted with ethyl acetate (20 mL×3)and the organic layers were combined and concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:2). This resulted in 76.0 mg (46%) of1-benzyl-N,N-dimethyl-4-[2-(methylsulfanyl)pyrimidin-4-yl]-1H-pyrazol-5-amineas light yellow oil. LC-MS (ES⁺): m/z 325.95 [M+H⁺], t_(R)=1.07 min,(1.9 minute run).

Step 6: Synthesis of1-benzyl-4-(2-methanesulfonylpyrimidin-4-yl)-N,N-dimethyl-1H-pyrazol-5-amine

Into a 25-mL round-bottom flask, was placed a solution of1-benzyl-N,N-dimethyl-4-[2-(methylsulfanyl)pyrimidin-4-yl]-1H-pyrazol-5-amine(76.0 mg, 0.23 mmol, 1.00 equiv) in dichloromethane (10 mL). To thissolution was added 3-chlorobenzoperoxoic acid (172.0 g, 996.70 mmol).The resulting solution was stirred for 2 h at room temperature. Thereaction was then quenched by the addition of water (20 mL). Theresulting solution was extracted with dichloromethane (20 mL×3) and theorganic layers were combined and concentrated under vacuum. Thisresulted in 76.0 mg (91%) of1-benzyl-4-(2-methanesulfonylpyrimidin-4-yl)-N,N-dimethyl-1H-pyrazol-5-amineas a light yellow solid. LC-MS (ES⁺): m/z 358.00[MH⁺], t_(R)=0.86 min,(1.9 minute run).

Step 7: Synthesis of2-(2-(2-(1,4-trans)-4-aminocyclohexyloxy)-ethoxy)ethoxy)ethanol

To a solution of2-(2-(2-((1,4-trans)-4-(dibenzylamino)cyclohexyloxy)-ethoxy)-ethoxy)-ethanol(512.0 mg, 1.2 mol, 1.0 equiv) in 20 mL MeOH was added Pd/C (10%, 500mg) under nitrogen atmosphere in a 100 mL round bottom flask. Thereaction flask was vacuumed and charged with a hydrogen balloon. Thereaction mixture was stirred for 16 h at 50° C. under hydrogenatmosphere. After the reaction was done, the reaction mixture wasfiltered through a Celite pad and the filtrate was concentrated underreduced pressure. This resulted in 247 mg of2-[2-(2-[[(1,4-trans)-4-aminocyclohexyl]oxy]ethoxy)ethoxy]ethan-1-ol ascolorless oil. LC-MS (ES⁺): m/z 248.10 [M+H⁺], t_(R)=0.55 min, (2.6minute run).

Step 8: Synthesis of2-(2-(2-((1,4-trans)-4-(4-(1-benzyl-5-(dimethylamino)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)cyclohexyloxy)ethoxy)ethoxy)ethanol

Into a 20 mL microwave vial, was placed a solution of2-[2-(2-[[(1,4-trans)-4-aminocyclohexyl]oxy]ethoxy)ethoxy]ethan-1-ol(247.0 mg, 1.0 mmol, 1.0 equiv) in iso-propanol (3.0 mL),1-benzyl-4-(2-methanesulfonylpyrimidin-4-yl)-N,N-dimethyl-1H-pyrazol-5-amine(357.0 mg, 1.0 mmol, 1.0 equiv), N,N-Diisopropylethylamine (516.0 mg,4.0 mmol, 4.0 equiv). The vial was irradiated in a microwave at 130° C.for 6 h. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column eluting with ethylacetate/petroleum ether (1:1). This resulted in 230.0 mg (44%) of2-[2-(2-[[(1,4-trans)-4-([4-[1-benzyl-5-(dimethylamino)-1H-pyrazol-4-yl]pyrimidin-2-yl]amino)cyclohexyl]-oxy]ethoxy)ethoxy]ethan-1-olas colorless oil. LC-MS (ES⁺): m/z 525.10 [M+H⁺], t_(R)=0.75 min, (2.0minute run).

Step 9: Synthesis of2-[2-(2-[[(1,4-trans)-4-([4-[1-benzyl-5-(dimethylamino)-1H-pyrazol-4-yl]pyrimidin-2-yl]amino)cyclohexyl]oxy]ethoxy)ethoxy]ethyl4-methylbenzene-1-sulfonate

Into a 100-mL round-bottom flask, was placed a solution of2-[2-(2-[[(1,4-trans)-4-([4-[1-benzyl-5-(dimethylamino)-1H-pyrazol-4-yl]pyrimidin-2-yl]amino)cyclohexyl]oxy]ethoxy)ethoxy]ethan-1-ol(105.0 mg, 0.2 mmol, 1.0 equiv) in dichloromethane (20.0 mL),triethylamine (40.0 mg, 0.4 mmol, 2.0 equiv), 4-dimethylaminopyridine(12.0 mg, 0.10 mmol, 0.1 equiv), 4-toluene sulfonyl chloride (57.0 mg,0.3 mmol, 1.5 equiv). The resulting solution was stirred for 4 h at 40°C. in an oil bath. The resulting solution was quenched with 15 ml ofwater and extracted with dichloromethane (20 mL×2). The combined organiclayers was dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was applied onto a silica gel column eluting withethyl acetate/petroleum ether (1:1). This resulted in 110 mg (81%) of2-[2-(2-[[(1,4-trans)-4-([4-[1-benzyl-5-(dimethylamino)-1H-pyrazol-4-yl]pyrimidin-2-yl]amino)cyclohexyl]oxy]-ethoxy)ethoxy]ethyl4-methylbenzene-1-sulfonate as colorless oil. LC-MS (ES⁺): m/z 679.35[M+H⁺], t_(R)=1.34 min, (2.0 minute run).

Step 10 through Step 12: Preparation of3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[2-methoxy-5-({2-[2-(2-{[(1r,4r)-4-({4-[1-benzyl-5-(dimethylamino)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)cyclohexyl]oxy}-ethoxy)ethoxy]ethyl}carbamoyl)phenyl]pyrrolidine-2-carboxamide(A2766)

The preparation of A2766 from the intermediate prepared in step 9 wascarried out using the same method descried for the preparation of A1717,namely, the conversion of the tosyl group to amine and followed by amideformation with MDM2 ligand.

¹H NMR (400 MHz, CD₃OD, ppm) δ 8.43-8.38 (m, 1H), 8.21-8.15 (m, 1H),7.95 (s, 1H), 7.75-7.65 (m, 1H), 7.58 (s, 1H), 7.51-7.45 (m, 1H),7.41-7.28 (m, 10H), 6.88-6.83 (m, 1H), 5.33 (s, 2H), 4.78-4.73 (m, 1H),4.65-4.56 (m, 1H), 4.11-4.05 (m, 1H), 3.99 (s, 3H), 3.98-3.85 (m, 1H),3.72-3.3.67 (m, 6H), 3.66-3.58 (m, 6H), 2.79 (s, 6H), 2.11-2.01 (m, 4H),1.74-1.65 (m, 1H), 1.41-1.23 (m, 6H), 1.03 (s, 9H).

LC-MS calcd for C₅₉H₆₈Cl₂F₂N₁₀O₆ (m/z) 1120.47, obsd 1121.50 (M+H⁺);t_(R)=3.40 min (5.0 minute run).

Compound A2720, A2791 and A2792 were prepared with the same method asdescribed for the preparation of A2766.

Protein Degradation Biological Assays

The following biological assays were performed to evaluate the proteindegradation in various cell types using representative compoundsdisclosed. In each assay, cells were treated with varying amounts ofcompounds encompassed by the current disclosure as shown in the Table.The degradation of the following proteins were evaluated:bromodomain-containing protein 4 (BRD4), androgen receptor (AR), c-Myc,c-Jun N-terminal kinases (JNK), and enhancer of zeste homolog 2 (EZH2).

BRD4 Western Blot

VCaP cells were chased from ATCC and cultured in Dulbecco's ModifiedEagle's Medium (ATCC), supplemented with 10% FBS (ATCC) andPenicillin/Streptomycin (Life Technologies). DMSO control and compoundtreatments (0.03 μM to 1 μM) were performed in 12-well plates for 16 h.cells were harvested, and lysed in RIPA buffer (50 mM Tris pH8, 150 mMNaCl, 1% Tx-100, 0.1% SDS, 0.5% sodium deoxycholate) supplemented withprotease and phosphatase inhibitors. Lysates were clarified at 16,000 gfor 10 minutes, and protein concentration was determined. Equal amountof protein (20 μg) was subjected to SDS-PAGE analysis and followed byimmunoblotting according to standard protocols. The antibodies used wereBRD4 (Cell signaling #13440), and Actin (Sigma #5441). Detectionreagents were Clarity Western ELC substrate (Bio-rad #170-5060).

AR ELISA Assay

VCaP cells were chased from ATCC and cultured in Dulbecco's ModifiedEagle's Medium (ATCC), supplemented with 10% FBS (ATCC) andPenicillin/Streptomycin (Life Technologies). DMSO control and compoundtreatments (0.0001 μM to 1 μM) were performed in 96-well plates for 16h. cells were harvested, and lysed with Cell Lysis Buffer (catalog#9803) (20 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1 mM Na₂EDTA, 1 mM EGTA, 1%Triton, 2.5 mM sodium pyrophosphate, 1 mM B-glycerophosphate, 1 mMNa₃VO₄, 1 μg/mL leupeptin. Lysates were clarified at 16,000 g for 10minutes, and loaded into PathScan AR ELISA (Cell Signaling Catalog#12850). The PathScan Total Androgen Receptor Sanwich ELISA Kit is asolid phase sandwich enzyme-linked immunosorbent assay (ELISA) thatdetects endogenous levels of total androgen receptor protein. AnAndrogen Receptor Rabbit mAb has been coated onto the microwells. Afterincubation with cell lysates, androgen receptor protein is captured bythe coated antibody. Following extensive washing, an Androgen receptorMouse Detection mAbis added to detect the captured androgen receptorprotein. Anti-mouse IgG, HRP-linked Antibody is then used to recognizethe bound detection antibody. HRP substrate, TMB, is added to developcolor. The magnitude of absorbance for the developed color isproportional to the quantity of total androgen receptor protein.

c-Myc ELISA Assay

22Rv-1 cells were purchased from ATCC and cultured in RPMI with 10% FBS.Cells were harvested using trypsin (Gibco #25200-114), counted andseeded at 30,000 cells/well at a volume of 75 μL/well in RPMI with 10%FBS in 96-well plates. Cells were dosed with compounds diluted in 0.1%DMSO, incubated for 18 h, then washed and lysed in 50 μL RIPA buffer (50mM Tris pH 8, 150 mM NaCl, 1% Tx-100, 0.1% SDS, 0.5% sodiumdeoxycholate) supplemented with protease and phosphatase inhibitors. Thelysates were clarified at 4000 rpm at 4° C. for 10 minutes. Aliquotswere added into a 96-well ELISA plate of Novex Human c-Myc ELISA kitfrom Life Technologies (catalog # KH02041). Into each well was added 50μL of c-Myc detection antibody. Plates were incubated at roomtemperature for 3 h, washed with ELISA wash buffer, followed by additionof 100 μL of the anti-rabbit IgG-HRP secondary antibody and 30 minutesof incubation. The plates were washed with ELISA wash buffer followed byaddition of 100 μL of TMB to each well. Color change was monitored every5 minutes. Stop solution (100 μL) was added and plates were read at 450nM.

JNK and EZH2 Western Blot Assay

Cells were purchased from ATCC and cultured in Dulbecco's ModifiedEagle's Medium (ATCC), supplemented with 10% FBS (ATCC) andPenicillin/Streptomycin (Life Technologies). DMSO control and compoundtreatments (0.003 μM, 0.01 μM, 0.03 μM and 0.1 μM) were performed in12-well plates for 16 h. Cells were harvested, and lysed in RIPA buffer(50 mM Tris pH8, 150 mM NaCl, 1% Tx-100, 0.1% SDS, 0.5% sodiumdeoxycholate) supplemented with protease and phosphatase inhibitors.Lysates were clarified at 16,000 g for 10 minutes, and proteinconcentration was determined. Equal amount of protein (20 μg) wassubjected to SDS-PAGE analysis and followed by immunoblotting accordingto standard protocols.

Synthesized molecules were assayed for protein degradation, suppression,and regulation and growth inhibition of cancer cells (FIG. 1). c-Mycsuppression was observed in 22rv1 cells by chimeric molecules, whereBRD4 ligand is connected through linkers to MDM2 ligands using partialstructural motif in RG7388. Chimeric molecules with inactive MDM2 ligand(enantiomer of the active counterpart) demonstrated no c-Myc suppressionacross a range of concentrations, while chimeric molecules with activeMDM2 ligand showed dose dependent c-Myc suppression, suggesting BRD4degradation mediated by MDM2 E3 ligase ubiquitination mechanism, asc-Myc is directly regulated by the level of BRD4. Chimeric moleculeswith MDM2 ligand as a racemate displayed similar c-Myc suppression asobserved in those containing active MDM2 ligand.

Western blot of HCT116 cells treated with chimeric molecules wasperformed, where BRD4 ligand is connected through linkers to MDM2ligands using partial structural motif in RG7388 (FIG. 2). Chimericmolecules with inactive MDM2 ligand (A-1891, A-1894) demonstrated no p53level increase and no MDM2 up-regulation, while chimeric molecules withactive MDM2 ligand (A-1864, A1892 and A-1893, A-1877 carried a racemicMDM2 binding ligand) showed dose dependent p53 level increase andup-regulation of MDM2, suggesting chimeric molecules with BRD4 bindingfragment and MDM2 binding fragment connected through a linker canfunction as small molecule MDM2 antagonist in stabilizing p53. The lesssignificant MDM2 up regulation and p53 level increase is due to thechimeric molecule action mechanism of not only binding to MDM2 to blockp53-MDM2 interaction but also degrading MDM2. Therefore, the net MDM2up-regulation is significantly less, which also translated to p53 leveldue to MDM2-p53 feedback loop.

Western blot of HCT116 cells treated with chimeric molecules (FIG. 3),where MDM2 ligand (using partial structural motif of RG7388) isconnected through linkers to VHL ligand. Chimeric molecules withinactive MDM2 ligand (A-1897, A1908, and A-1911) demonstrated no p53level increase and no MDM2 up-regulation, while chimeric molecules withactive MDM2 ligand (A-1896, A-1907, and A-1910, with A-1877, A-1895, andA-1909 carrying a racemic MDM2 binding ligand) showed dose dependent p53level increase.

In p53^(WT) HCT-116 colon cancer cell lines, MDM2-recruiting BRD-4PROTAC with active MDM2 binding moiety (A-1893) caused very potentgrowth inhibition in comparison with the MDM2-recruiting BRD-4 PROTACwith inactive MDM2 binding moiety (A-1894) (FIG. 4). In this cell growthassay, BRD4-Cereblon PROTAC A-825, MDM2 antagonist RG7388 (A-1850), theracemate of RG7388 (A-1851) and JQ1 were included as a directcomparison.

Time course of BRD4 degradation caused by BRD4-MDM2 chimeric compound(A-1893) in human colon cancer cell line HCT116 (FIG. 5) and human lungcancer cell line A549. (FIG. 6)

Following table is a representative of the degradation activity of someexemplary compounds. The degradation activities for target proteins arecategorized as following: A (0 to 25% degradation at 1 μM); B (25 to 50%degradation at 1 μM) and C (larger than 50% degradation at 1 μM).

Observed (m/z) Degradation activity Example from LC/MS BRD4 AR JNK EZH2Chemical Name A680 1082 A 4-(3-{4-[2-(2-{4-[2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole- 1-carbonyl]piperazin-1-yl}ethoxy)ethoxy]phenyl}-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1- yl)-2-(trifluoromethyl)benzonitrileA702 1260 B 4-(3-{4-[(17-{4-[2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole-1-carbonyl]piperazin-1-yl}-3,6,9,12,15-pentaoxaheptadecan-1-yl)oxy]phenyl}-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile A1283 1135, 1137 BN-(17-{[3-(3-chloro-2-fluorophenyl)-4- (M + Na)(4-chloro-2-fluorophenyl)-4-cyano-5- (2,2-dimethylpropyl)pyrrolidin-2-yl]formamido}-3,6,9,12,15- pentaoxaheptadecan-1-yl)-2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo-[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide A1306 1025, 1027 BN-(2-{2-[2-(2-{[3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidin-2-yl]formamido}ethoxy)ethoxy]ethoxy}ethyl)-2-[(9S)-7-(4-chlorophenyl)-4,5,13- trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide A1307 1069, 1071 CN-(14-{[3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5- (2,2-dimethylpropyl)pyrrolidin-2-yl]formamido}-3,6,9,12- tetraoxatetradecan-1-yl)-2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia- 1,8,11,12-tetraazatricyclo-[8.3.0.0²,⁶]trideca-2(6),4,7,10,12- pentaen-9-yl]acetamide A1571 934,936 A 3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2- dimethylpropyl)-N-{2-[2-(4-{[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)- 2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenoxy)ethoxy]ethyl}pyrrolidine- 2-carboxamide A1603 1024,1026 A 3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2- dimethylpropyl)-N-[1-(4-{[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenyl)-1,4,7,10-tetraoxadodecan-12-yl]pyrrolidine- 2-carboxamide A1621 980, 982A 3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2- dimethylpropyl)-N-(2-{2-[2-(4-{[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)- 2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenoxy)ethoxy]ethoxy}ethyl)pyr- rolidine-2-carboxamide A16881112, 1114 A 3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5- (2,2-dimethylpropyl)-N-[1-(4-{[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)- 2,2,4,4-tetramethylcyclobutyl]-carbamoyl}phenyl)-1,4,7,10,13,16- hexaoxaoctadecan-18-yl]pyrrolidine-2-carboxamide A1717 1068, 1070 B 3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2- dimethylpropyl)-N-[1-(4-{[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenyl)-1,4,7,10,13-pentaoxapentadecan-15- yl]pyrrolidine-2-carboxamide A17201068, 1070 B (2R,3S,4R,5S)-3-(3-chloro-2- fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2- dimethylpropyl)-N-[1-(4-{[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenyl)-1,4,7,10,13-pentaoxapentadecan-15- yl]pyrrolidine-2-carboxamide A17351068, 1070 A (2S,3R,4S,5R)-3-(3-chloro-2- fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2- dimethylpropyl)-N-[1-(4-{[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- tetramethylcyclobutyl]carbamoyl}phenyl)-1,4,7,10,13-pentaoxapentadecan-15- yl]pyrrolidine-2-carboxamide A18291174, 1176 B 3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-{4-[(2-{2-[2-(2-{2- [(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12- tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}ethoxy)ethoxy]ethoxy}ethyl)carbamoyl]-2-methoxyphenyl}-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide A1863 1130, 1132 B3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-[4-({2-[2-(2-{2- [(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12- tetraazatricyclo-[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-9- yl]acetamido}ethoxy)ethoxy]-ethyl}carbamoyl)-2-methoxyphenyl]-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine- 2-carboxamide A1864 1130, 1132B (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-[4-({2-[2-(2-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo-[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}ethoxy)ethoxy]ethyl}- carbamoyl)-2-methoxyphenyl]-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide A1865 1130, 1132 A(2S,3R,4S,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-[4-({2-[2-(2-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo-[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}ethoxy)ethoxy]ethyl}-carbamoyl)-2-methoxyphenyl]-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide A1874 1172, 1174 B(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-{4-[(2-{2-[2-(2-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}ethoxy)ethoxy]ethoxy}ethyl)carbamoyl]-2-methoxyphenyl}-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide A1875 1172, 1174 A(2S,3R,4S,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-{4-[(2-{2-[2-(2-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}ethoxy)ethoxy]ethoxy}ethyl)carbamoyl]-2-methoxyphenyl}-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide A1876 1216, 1218 C3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-{4-[(14-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]-trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}-3,6,9,12-tetraoxatetradecan-1-yl)carbamoyl]-2-methoxyphenyl}-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide A1877 1173, 11753-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[4-({2-[2-({[(2S)-1-[(2S,4R)-4-hydroxy-2- ({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methoxy)ethoxy]ethyl}carbamoyl)-2-methoxyphenyl]pyrrolidine-2-carboxamide A1890 1084, 1086 C3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-(4-{[2-(2-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]-trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}ethoxy)ethyl]carbamoyl}-2-methoxyphenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide A1891 1084, 1086 A(2S,3R,4S,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-(4-{[2-(2-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]-trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}ethoxy)ethyl]carbamoyl}-2-methoxyphenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide A1892 1084, 1086 C(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-(4-{[2-(2-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]-trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}ethoxy)ethyl]carbamoyl}-2-methoxyphenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide A1893 1216, 1218 C(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-{4-[(14-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]-trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}-3,6,9,12-tetraoxatetradecan-1-yl)carbamoyl]-2-methoxyphenyl}-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide A1894 1216, 1218 A(2S,3R,4S,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-{4-[(14-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]-trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}-3,6,9,12-tetraoxatetradecan-1-yl)carbamoyl]-2-methoxyphenyl}-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide A1895 1261, 12633-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-{4-[(1-{[(2S)-1-[(2S,4R)4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}-2,5,8,11-tetraoxatridecan-13-yl)carbamoyl]-2-methoxyphenyl}pyrrolidine-2-carboxamide A1896 1261, 1263(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-{4-[(1-{[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}-carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}-2,5,8,11-tetraoxatridecan-13-yl)carbamoyl]-2-methoxyphenyl}pyrrolidine-2-carboxamide A1897 1261, 1263(2S,3R,4S,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-{4-[(1-{[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}-carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}-2,5,8,11-tetraoxatridecan-13-yl)carbamoyl]-2-methoxyphenyl}pyrrolidine- 2-carboxamide A1907 1173,1175 (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[4-({2-[2-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}-carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methoxy)-ethoxy]ethyl}carbamoyl)-2-methoxyphenyl]pyrrolidine-2-carboxamide A1908 1173, 1175(2S,3R,4S,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[4-({2-[2-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}-carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methoxy)-ethoxy]ethyl}carbamoyl)-2-methoxyphenyl]pyrrolidine-2-carboxamide A1909 1217, 12193-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-{4-[(2-{2-[2-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin- 1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methoxy)ethoxy]ethoxy}ethyl)carbamoyl]-2-methoxyphenyl}-pyrrolidine-2-carboxamide A1910 1217, 1219(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-{4-[(2-{2-[2-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}-carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methoxy)-ethoxy]ethoxy}ethyl)carbamoyl]-2-methoxyphenyl}pyrrolidine-2-carboxamide A1911 1217, 1219(2S,3R,4S,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-{4-[(2-{2-[2-({[(2S)-1-[(2S,4R)- 4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}-carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methoxy)-ethoxy]ethoxy}ethyl)carbamoyl]-2-methoxyphenyl}pyrrolidine-2-carboxamide A2434 997, 999 C3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(3-{[5-(4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}phenoxy)pentyl]oxy}propyl)-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide A2435 1146, 1148 C3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-{4-[(3-{[5-(4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}phenoxy)pentyl]oxy}propyl)carbamoyl]-2-methoxyphenyl}-5-(2,2-dimethylpropyl)pyrrolidine- 2-carboxamide A27201077 A 3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-(2-methoxy-4-{[2-(2-{[(1,4-trans)-4-({4-[1-benzyl-5-(dimethylamino)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)cyclohexyl]oxy}ethoxy)ethyl]carbamoyl}phenyl)pyrrolidine-2-carboxamide A2766 1121 A3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[2-methoxy-5-({2-[2-(2-{[(1,4-trans)-4-({4-[1-benzyl-5-(dimethylamino)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)cyclo-hexyl]oxy}ethoxy)ethoxy]ethyl}carbamoyl)phenyl]pyr-rolidine-2-carboxamide A2790 1264 A3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-[4-({1-[4-(3-{[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]carbamoyl}-5-[ethyl(oxan-4-yl)amino]-4-methylphenyl)phenyl]-1,4,7,10-tetraoxadodecan-12-yl}carbamoyl)-2-methoxyphenyl]-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide A2791 1165 A3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[2-methoxy-4-({1-[(1,4-trans)-4-({4-[1-benzyl-5-(dimethylamino)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)cyclohexyl]-1,4,7,10-tetraoxadodecan-12-yl}carbamoyl)phenyl]pyrrolidine-2-carboxamide A2792 1209 A3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[2-methoxy-5-({1-[(1,4-trans)-4-({4-[1-benzyl-5-(dimethylamino)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)cyclohexyl]-1,4,7,10,13-pentaoxapentadecan-15-yl}carbamoyl)phenyl]pyrrolidine-2-carboxamide A2844 1352 A3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-[4-({1-[4-(3-{[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]carbamoyl}-5-[ethyl(oxan-4-yl)amino]-4-methylphenyl)phenyl]-1,4,7,10,13,16-hexaoxaoctadecan-18-yl}carbamoyl)-2-methoxyphenyl]-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide

1. A compound having a chemical structure comprising of:PTM-L-MLM wherein MLM is a MDM2 E3 ubiquitin ligase binding moiety, PTMis a protein targeting moiety, and L is a linker coupling the MLM to thePTM, and wherein the PTM binds to a targeted protein having a functionor activity selected from the group consisting of: structural protein,regulatory, growth factor, receptor, cytoskeletal, hormonal, enzymatic,nucleic acid binding, immunological, contractile, storage,transportation, signal transduction, catalytic activity, proteinbinding, aromatase activity, lipase, protease, nuclease, motor activity,helicase activity, metabolism, antioxidant activity, proteolysis,biosynthesis, kinase, oxidoreductase, transferase, hydrolase, lyase,isomerase, ligase, enzyme regulator, signal transducer, protein or lipidbinding, cell motility, membrane fusion, cell communication, cell growthor differentiation, cell division, response to stimulus, cell adhesion,apoptosis, transport, secretion, electron transport, ion channel,chaperone or chaperone regulator, nucleic acid binding activity,transcription regulator, extracellular organization and biogenesis, andtranslation regulator, or a pharmaceutically acceptable salt,enantiomer, stereoisomer, solvate, polymorph or prodrug thereof.
 2. Thecompound of claim 1, wherein the PTM binds to a protein selected fromthe group consisting of B7.1, B7, TINFR1m, TNFR2, NADPH oxidase, Bcl,Bax, apotosis pathway proteins, C5a receptor, HMG-CoA reductase, PDE Vphosphodiesterase, PDE IV phosphodiesterase, PDE I, PDEII, PDEIII,squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase,cyclo-oxygenase 1, cyclo-oxygenase 2, 5HT receptor, dopamine receptor, GProtein, Gq, histamine receptor, 5-lipoxygenase, tryptase serineprotease, thymidylate synthase, purine nucleoside phosphorylase, GAPDHtrypanosomal, glycogen phosphorylase, carbonic anhydrase, chemokinereceptor, JAK, STAT, RXR, HIV 1 protease, HIV 1 integrase, influenza,neuramimidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosinekinase, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor,IL-1 receptor, TNF-alphaR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin,selectin, CD40/CD40L, receptor, inosine monophosphate dehydrogenase, p38MAP Kinase, JNK, Ras, Raf, ERK, FLT-3, KSR1, SMARCA, SMARCA2,interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNAhelicase, glycinamide ribonucleotide formyl transferase, rhinovirus 3Cprotease, herpes simplex virus-1 (HSV-I), protease, cytomegalovirus(CMV) protease, poly (ADP-ribose) polymerase, cyclin dependent kinase,growth factor, growth factor receptor, receptor tyrosine kinase,cytokine, GPCR, vascular endothelial growth factor, EGF, EGFR, HGF,HGFR, VEGF, VEGFR, Wnt, TNF-α, TPO, TCGF, PGF, NT-3, NT-4, TGF, TGF-β,oxytocin receptor, microsomal transfer protein inhibitor, bile acidtransport inhibitor, 5 alpha reductase, angiotensin 11, glycinereceptor, noradrenaline reuptake receptor, endothelin receptor,neuropeptide Y and receptor, estrogen receptor, androgen receptor,adenosine receptor, adenosine kinase and AMP deaminase, purinergicreceptor, P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7, an E1, E2 or E3 ubiquitinligase, VHL, cereblon, p53, farnesyltransferase, geranylgeranyltransferase, TrkA a receptor for NGF, beta-amyloid, tyrosine kinaseFlk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neu,telomerase, cytosolic phospholipaseA2 and EGF receptor tyrosine kinase,ecdysone 20-monooxygenase, GABA gated chloride channel,acetylcholinesterase, voltage-sensitive sodium channel protein, calciumrelease channel, chloride channel, Acetyl-CoA carboxylase,adenylosuccinate synthetase, protoporphyrinogen oxidase,enolpyruvylshikimate-phosphate synthase, haloalkane halogenaseinhibitors, Hsp90, kinase, MDM2, human BET Bromodomain-containingprotein, HDAC, EZH2, human lysine methyltransferase, and arylhydrocarbon receptor (AHR).
 3. The compound of claim 1, wherein the PTMbinds to a protein selected from the group consisting of a kinases,enzymes, transporters, nuclear hormone receptors, non-nuclear hormonereceptors, G-protein coupled receptors (GPCRs), transcription factors,and epigenetic targets particularly, a human BET Bromodomain-containingprotein (BRD), Brd4, Ras, Raf, MDM2, androgen receptor (AR) and estrogenreceptor (ER), EZH2 and JNK.
 4. A compound having a structure selectedfrom the group consisting of:

wherein, PTM is a protein targeting moiety that binds a target protein,and L is a linker coupling the PTM to the molecule shown; X is selectedfrom the group consisting of carbon, oxygen, sulfur, sulfoxide, sulfone,and N—R^(a); R^(a) is independently H or an alkyl group with carbonnumber 1 to 6; Y and Z are independently carbon or nitrogen; A, A′ andA″ are independently selected from C, N, O or S, can also be one or twoatoms forming a fused bycyclic ring, or a 6,5- and 5,5-fused aromaticbicyclic group; R₁, R₂ are independently selected from the groupconsisting of an aryl or heteroaryl group, a heteroaryl group having oneor two heteroatoms independently selected from sulfur or nitrogen,wherein the aryl or heteroaryl group can be mono-cyclic or bi-cyclic, orunsubstituted or substituted with one to three substituentsindependently selected from the group consisting of: halogen, —CN, C1 toC6 alkyl group, C3 to C6 cycloalkyl, —OH, alkoxy with 1 to 6 carbons,fluorine substituted alkoxy with 1 to 6 carbons, sulfoxide with 1 to 6carbons, sulfone with 1 to 6 carbons, ketone with 2 to 6 carbons, amideswith 2 to 6 carbons, and dialkyl amine with 2 to 6 carbons; R₃, R₄ areindependently selected from the group consisting of H, methyl and C1 toC6 alkyl; R₅ is selected from the group consisting of an aryl orheteroaryl group, a heteroaryl group having one or two heteroatomsindependently selected from sulfur or nitrogen, wherein the aryl orheteroaryl group can be mono-cyclic or bi-cyclic, or unsubstituted orsubstituted with one to three substituents independently selected fromthe group consisting of: halogen, —CN, C1 to C6 alkyl group, C3 to C6cycloalkyl, —OH, alkoxy with 1 to 6 carbons, fluorine substituted alkoxywith 1 to 6 carbons, sulfoxide with 1 to 6 carbons, sulfone with 1 to 6carbons, ketone with 2 to 6 carbons, amides with 2 to 6 carbons, dialkylamine with 2 to 6 carbons, alkyl ether (C2 to C6), alkyl ketone (C3 toC6), morpholinyl, alkyl ester (C3 to C6), alkyl cyanide (C3 to C6); R₆is H or —C(═O)R^(b), wherein R^(b) is selected from the group consistingof alkyl, cycloalkyl, mono-, di- or tri-substituted aryl or heteroaryl,4-morpholinyl, 1-(3-oxopiperazunyl), 1-piperidinyl,4-N—R^(c)-morpholinyl, 4-R^(c)-1-piperidinyl, and 3-R^(c)-1-piperidinyl,wherein R^(c) is selected from the group consisting of alkyl, fluorinesubstituted alkyl, cyano alkyl, hydroxyl-substituted alkyl, cycloalkyl,alkoxyalkyl, amide alkyl, alkyl sulfone, alkyl sulfoxide, alkyl amide,aryl, heteroaryl, mono-, bis- and tri-substituted aryl or heteroaryl,CH2CH2R^(d), and CH2CH2CH2R^(d), wherein R^(d) is selected from thegroup consisting of alkoxy, alkyl sulfone, alkyl sulfoxide,N-substituted carboxamide, —NHC(O)-alkyl, —NH—SO₂-alkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl; R₇ is selectedfrom the group consisting of H, C1 to C6 alkyl, cyclic alkyl, fluorinesubstituted alkyl, cyano substituted alkyl, 5- or 6-membered hetero arylor aryl, substituted 5- or 6-membered hetero aryl or aryl; R₈ isselected from the group consisting of —R^(e)—C(O)—R^(f), —R^(e)-alkoxy,—R^(e)-aryl, —R^(e)-heteroaryl, and —R^(e)—C(O)—R^(f)—C(O)—R^(g),wherein: R^(e) is an alkylene with 1 to 6 carbons, or a bond; R^(f) is asubstituted 4- to 7-membered heterocycle; R^(g) is selected from thegroup consisting of aryl, hetero aryl, substituted aryl or heteroaryl,and 4- to 7-membered heterocycle; R₉ is selected from the groupconsisting of a mono-, bis- or tri-substituent on the fused bicyclicaromatic ring in Formula (A-3), wherein the substitutents areindependently selected from the group consistin of halogen, alkene,alkyne, alkyl, unsubstituted or substituted with Cl or F; R₁₀ isselected from the group consistin of an aryl or heteroaryl group,wherein the heteroaryl group can contain one or two heteroatoms assulfur or nitrogen, aryl or heteroaryl group can be mono-cyclic orbi-cyclic, the aryl or heteroaryl group can be unsubstituted orsubstituted with one to three substituents, including a halogen, F, Cl,—CN, alkene, alkyne, C1 to C6 alkyl group, C1 to C6 cycloalkyl, —OH,alkoxy with 1 to 6 carbons, fluorine substituted alkoxy with 1 to 6carbons, sulfoxide with 1 to 6 carbons, sulfone with 1 to 6 carbons,ketone with 2 to 6 carbons; R₁₁ is —C(O)—N(R^(h))(R^(i)), wherein R^(h)and R^(i) are selected from groups consisting of the following: H, C1 toC6 alkyl, alkoxy substituted alkyl, sulfone substituted alkyl, aryl,heterol aryl, mono-, bis- or tri-substituted aryl or hetero aryl, alkylcarboxylic acid, heteroaryl carboxylic acid, alkyl carboxylic acid,fluorine substituted alkyl carboxylic acid, aryl substituted cycloalkyl,hetero aryl substituted cycloalkyl; wherein R^(h) and R^(i) areindependently selected from the group consisting of H, connected to forma ring, 4-hydroxycyclohehexane; mono- and di-hydroxy substituted alkyl(C3 to C6); 3-hydroxycyclobutane; phenyl-4-carboxylic acid, andsubstituted phenyl-4-carboxylic acid; R₁₂ and R₁₃ are independentlyselected from H, lower alkyl (C1 to C6), lower alkenyl (C2 to C6), loweralkynyl (C2 to C6), cycloalkyl (4, 5 and 6-membered ring), substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, 5- and 6-memberedaryl and heteroaryl, R12 and R13 can be connected to form a 5- and6-membered ring with or without substitution on the ring; R₁₄ isselected from the group consisting of alkyl, substituted alkyl, alkenyl,substituted alkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocycle, substituted heterocycle, cycloalkyl,substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; R₁₅is CN; R₁₆ is selected from the group consisting of C1-6 alkyl, C1-6cycloalkyl, C2-6 alkenyl, C1-6 alkyl or C3-6 cycloalkyl with one ormultiple hydrogens replaced by fluorine, alkyl or cycloalkyl with oneCH₂ replaced by S(═O), —S, or —S(═O)₂, alkyl or cycloalkyl with terminalCH₃ replaced by S(═O)₂N(alkyl)(alkyl), —C(═O)N(alkyl)(alkyl),—N(alkyl)S(═O)₂(alkyl), —C(═O)2(allkyl), —O(alkyl), C1-6 alkyl oralkyl-cycloalkyl with hydron replaced by hydroxyl group, a 3 to 7membered cycloalkyl or heterocycloalkyl, optionally containing a—(C=0)-group, or a 5 to 6 membered aryl or heteroaryl group, whichheterocycloalkyl or heteroaryl group can contain from one to threeheteroatoms independently selected from O, N or S, and the cycloalkyl,heterocycloalkyl, aryl or heteroaryl group can be unsubstituted orsubstituted with from one to three substituents independently selectedfrom halogen, C1-6 alkyl groups, hydroxylated C1-6 alkyl, C1-6 alkylcontaining thioether, ether, sulfone, sulfoxide, fluorine substitutedether or cyano group; R₁₇ is selected from the group consisting of(CH₂)nC(O)NR^(k)R^(l), wherein R^(k) and R^(l) are independentlyselected from H, C1-6 alkyl, hydrxylated C1-6 alkyl, C1-6 alkoxy alkyl,C1-6 alkyl with one or multiple hydrogens replaced by fluorine, C1-6alkyl with one carbon replaced by S(O), S(O)(O), C1-6 alkoxyalkyl withone or multiple hydrogens replaced by fluorine, C1-6 alkyl with hydrogenreplaced by a cyano group, 5 and 6 membered aryl or heteroaryl, aklylaryl with alkyl group containing 1-6 carbons, and alkyl heteroaryl withalkyl group containing 1-6 carbons, wherein the aryl or heteroaryl groupcan be further substituted; R₁₈ is selected from the group consisting ofsubstituted aryl, heteroaryl, alkyl, cycloalkyl, the substitution ispreferably —N(C1-4 alkyl)(cycloalkyl), —N(C1-4 alkyl)alkyl-cycloalkyl,and —N(C1-4 alkyl)[(alkyl)-(heterocycle-substituted)-cycloalkyl]; R₁₉ isselected from the group consisting of aryl, heteroaryl, bicyclicheteroaryl, and these aryl or hetroaryl groups can be substituted withhalogen, C1-6 alkyl, C1-6 cycloalkyl, CF₃, F, CN, alkyne, alkyl sulfone,the halogen substitution can be mon- bis- or tri-substituted; R₂₀ andR₂₁ are independently selected from C1-6 alkyl, C1-6 cycloalkyl, C1-6alkoxy, hydoxylated C1-6 alkoxy, and fluorine substituted C1-6 alkoxy,wherein R₂₀ and R₂₁ can further be connected to form a 5, 6 and7-membered cyclic or heterocyclic ring, which can further besubstituted; R₂₂ is selected from the group consisting of H, C1-6 alkyl,C1-6 cycloalkyl, carboxylic acid, carboxylic acid ester, amide, reverseamide, sulfonamide, reverse sulfonamide, N-acyl urea,nitrogen-containing 5-membered heterocycle, the 5-membered heterocyclescan be further substituted with C1-6 alkyl, alkoxy, fluorine-substitutedalkyl, CN, and alkylsulfone; R₂₃ is selected from aryl, heteroaryl,—O-aryl, —O-heteroaryl, —O-alkyl, —O-alkyl-cycloalkyl, —NH-alkyl,—NH-alkyl-cycloalkyl, —N(H)-aryl, —N(H)-heteroaryl, —N(alkyl)-aryl,—N(alkyl)-heteroaryl, the aryl or heteroaryl groups can be substitutedwith halogen, C1-6 alkyl, hydoxylated C1-6 alkyl, cycloalkyl,fluorine-substituted C1-6 alkyl, CN, alkoxy, alkyl sulfone, amide andsulfonamide; R₂₄ is selected from the group consisting of —CH2-(C1-6alkyl), —CH2-cycloalkyl, —CH2-aryl, CH2-heteroaryl, where alkyl,cycloalkyl, aryl and heteroaryl can be substituted with halogen, alkoxy,hydoxylated alkyl, cyano-substituted alkyl, cycloalyl and substitutedcycloalky; R₂₅ is selected from the group consisting of C1-6 alkyl, C1-6alkyl-cycloalkyl, alkoxy-substituted alkyl, hydroxylated alkyl, aryl,heteroaryl, substituted aryl or heteroaryl, 5,6, and 7-memberednitrogen-containing saturated heterocycles, 5,6-fused and 6,6-fusednitrogen-containing saturated heterocycles and these saturatedheterocycles can be substituted with C1-6 alkyl, fluorine-substitutedC1-6 alkyl, alkoxy, aryl and heteroaryl group; R₂₆ is selected from thegroup consisting of C1-6 alkyl, C3-6 cycloalkyl, the alkyl or cycloalkylcan be substituted with —OH, alkoxy, fluorine-substituted alkoxy,fluorine-substituted alkyl, —NH₂, —NH-alkyl, NH—C(O)alkyl,—NH—S(O)₂-alkyl, and —S(O)₂-alkyl; R₂₇ is selected from the groupconsisting of aryl, heteroaryl, bicyclic heteroaryl, wherein the aryl orheteroaryl groups can be substituted with C1-6 alkyl, alkoxy, NH2,NH-alkyl, halogen, or —CN, and the substitution can be independentlymono-, bis- and tri-substitution; R₂₈ is selected from the groupconsisting of aryl, 5 and 6-membered heteroaryl, bicyclic heteroaryl,cycloalkyl, saturated heterocycle such as piperidine, piperidinone,tetrahydropyran, N-acyl-piperidine, wherein the cycloalkyl, saturatedheterocycle, aryl or heteroaryl can be further substituted with —OH,alkoxy, mono-, bis- or tri-substitution including halogen, —CN, alkylsulfone, and fluorine substituted alkyl groups; and R_(1″) is selectedfrom the group consisting of alkyl, aryl substituted alkyl, alkoxysubstituted alkyl, cycloalkyl, aryl-substituted cycloalkyl, and alkoxysubstituted cycloalkyl, or a pharmaceutically acceptable salt,enantiomer, stereoisomer, solvate, polymorph or prodrug thereof.
 5. Thecompound of claim 4, wherein the heterocycles in R^(f) and R^(g) areindependently selected from the group consisting of substitutedpyrrolidine, substituted piperidine, and substituted piperizine.
 6. Thecompound of claim 4, wherein the R₉ substituents are selected from Cland F.
 7. The compound of claim 4, wherein the R₁₀ substituents areselected from H, F and Cl.
 8. The compound of claim 4, wherein R^(h) andR^(i) are selected from the group consisting of: (i) R^(h) is H, andR^(i) is 4-hydroxycyclohehexane; (ii) R^(h) is H, and R^(i) is mono- anddi-hydroxy substituted lower alkyl (C3 to C6); (iii) R^(h) is H, andR^(i) is 3-hydroxycyclobutane; and (iv) R^(h) is H, and R^(i) isphenyl-4-carboxylic acid, substituted phenyl-4-carboxylic acid.
 9. Thecompound of claim 4, wherein the R₁₈ substitution is selected from thegroup consisting of —N(C1-4 alkyl)(cycloalkyl), —N(C1-4alkyl)alkyl-cycloalkyl, and —N(C1-4 alkyl)[(alkyl)-(heterocycle-substituted)-cycloalkyl].
 10. The compound ofclaim 4, wherein the R₂₈ saturated heterocycle is selected frompiperidine, piperidinone, tetrahydropyran, and N-acyl-piperidine. 11.The compound of claim 4, wherein the compound has a structure selectedfrom the group consisting of:

wherein R1′ and R2′ are independently selected from the group consistingof F, Cl, Br, I, acetylene, CN, CF₃ and NO₂; R3′ is selected from thegroup consisting of —OCH₃, —OCH₂CH₃, —OCH₂CH₂F, —OCH₂CH₂OCH₃, and—OCH(CH₃)₂; R4′ and R6′ are independently selected from the groupconsisting of H, halogen, —CH₃, —CF₃, —OCH₃, —C(CH₃)₃, —CH(CH₃)₂,-cyclopropyl, —CN, —C(CH₃)₂OH, —C(CH₃)₂OCH₂CH₃, —C(CH₃)₂CH₂OH,—C(CH₃)₂CH₂OCH₂CH₃, —C(CH₃)₂CH₂OCH₂CH₂OH, —C(CH₃)₂CH₂OCH₂CH₃,—C(CH₃)₂CN, —C(CH₃)₂C(O)CH₃, —C(CH₃)₂C(O)NHCH₃, —C(CH₃)₂C(O)N(CH₃)₂,—SCH₃, —SCH₂CH₃, —S(O)₂CH₃, —S(O₂)CH₂CH₃, —NHC(CH₃)₃, —N(CH₃)₂,pyrrolidinyl, and 4-morpholinyl; and R5′ is selected from the groupconsisting of halogen, -cyclopropyl, —S(O)₂CH₃, —S(O)₂CH₂CH₃,1-pyrrolidinyl, —NH₂, —N(CH₃)₂, and —NHC(CH₃)₃, or a pharmaceuticallyacceptable salt, enantiomer, stereoisomer, solvate, polymorph or prodrugthereof.
 12. The compound of claim 11, wherein the linker is attached toat least one of R1′, R2′, R3′, R4′, R5′, R6′, or a combination thereof.13. The compound of claim 11, wherein R6′ is independently selected fromthe group consisting of H,

wherein * indicates the point of attachment of the linker.
 14. Thecompound of claim 4, wherein the compound has a structure selected fromthe group consisting of:

wherein R_(7′) is a member selected from the group consisting ofhalogen, mono-, and di- or tri-substituted halogen; R_(8′) is selectedfrom the group consisting of H, —F, —Cl, —Br, —I, —CN, —NO₂, ethylnyl,cyclopropyl, methyl, ethyl, isopropyl, vinyl, methoxy, ethoxy,isopropoxy, —OH, other C1-6 alkyl, other C1-6 alkenyl, and C1-6 alkynyl,mono-, di- or tri-substituted; R_(9′) is selected from the groupconsistin of alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, hetero aryl,substituted heteroaryl, cycloalkyl, substituted cycloalkyl, alkenyl, andsubstituted cycloalkenyl; Z is selected from the group consistin of H,—OCH₃, —OCH₂CH₃, and halogen; R_(10′) and R_(11′) are each independentlyselected from the group consisting of H, (CH₂)_(n)—R′, (CH₂)_(n)—NR′R″,(CH₂)_(n)—NR′COR″, (CH₂)_(n)—NR′SO₂R″, (CH₂)_(n)—COOH, (CH₂)_(n)—COOR′,(CH)_(n)—CONR′R″, (CH₂)_(n)—OR′, (CH₂)_(n)—SR′, (CH₂)_(n)—SOR′,(CH₂)_(n)—CH(OH)—R′, (CH₂)_(n)—COR′, (CH₂)_(n)—SO₂R′, (CH₂)_(n)—SONR′R″,(CH₂)_(n)—SO₂NR′R″, (CH₂CH₂O)_(m)—(CH₂)_(n)—R′,(CH₂CH₂O)_(m)—(CH₂)_(n)—OH, (CH₂CH₂O)_(m)—(CH₂)_(n)—OR′,(CH₂CH₂O)_(m)—(CH₂)_(n)—NR′R″, (CH₂CH₂O)_(m)—(CH₂)_(n)—NR′COR″,(CH₂CH₂O)_(m)(CH₂)_(n)—NR′SO₂R″, (CH₂CH₂O)_(m)(CH₂)_(n)—COOH,(CH₂CH₂O)_(m)(CH₂)_(n)—COOR′, (CH₂CH₂O)_(m)—(CH2)_(n)—CONR′R″,(CH₂CH₂O)_(m)—(CH₂)_(n)—SO₂R′, (CH₂CH₂O)_(m)—(CH₂)_(n)—COR′,(CH₂CH₂O)_(m)—(CH₂)_(n)—SONR′R″, (CH₂CH₂O)_(m)—(CH₂)_(n)—SO₂NR′R″,(CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)^(n)R′, (CH₂)p-(CH₂CH₂O)_(m)—(CH₂)_(n)—OH,(CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)n-OR′,(CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—NR′R″,(CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—NR′COR″, (CH₂)_(p)—(CH₂CH₂O)m-(CH₂)_(n)—NR′SO₂R″, (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—COOH,(CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—COOR′,(CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—CONR′R″,(CH₂)p-(CH₂CH₂O)_(m)—(CH₂)_(n)—SO₂R′,(CH2)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—COR′,(CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—SONR′R″,(CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—SO₂NR′R″, Aryl-(CH₂)_(n)—COOH, andheteroaryl-alkyl-CO-alkyl-NR′R″m, wherein the alkyl may be substitutedwith OR′, and heteroaryl-(CH₂)_(n)-heterocycle wherein the heterocyclemay optionally be substituted with alkyl, hydroxyl, COOR′ and COR′;wherein R′ and R″ are selected from H, alkyl, alkyl substituted withhalogen, hydroxyl, NH2, NH(alkyl), N(alkyl)₂, oxo, carboxy, clcloalkyland heteroaryl; m, n, and p are independently 0 to 6; R_(12′) isselected from the group consisting of —O-(alkyl), —O-(alkyl)-akoxy,—C(O)-(alkyl), —C(OH)-alkyl-alkoxy, —C(O)—NH-(alkyl), —C(O)—N-(alkyl)₂,—S(O)-(alkyl), S(O)₂-(alkyl), —C(O)-(cyclic amine), and —O-aryl-(alkyl),—O-aryl-(alkoxy); and R_(1″) is selected from the group consisting ofalkyl, aryl substituted alkyl, aloxy substituted alkyl, cycloalkyl,ary-substituted cycloalkyl, and alkoxy substituted cycloalkyl, or apharmaceutically acceptable salt, enantiomer, stereoisomer, solvate,polymorph or prodrug thereof.
 15. The compound of claim 14, wherein thelinker is attached to at least one of Z, R_(8′), R_(9′), R_(10′),R_(11′), R_(12′), R_(1″), or a combination thereof.
 16. The compound ofany of claim 4, 11 or 14, wherein the linker group (L) comprises achemical structural unit represented by the formula:-Aq- wherein: q is an integer greater than 1; and A is independentlyselected from the group consisting of a bond, CRL1RL2, O, S, SO, SO2,NRL3, SO2NRL3, SONRL3, CONRL3, NRL3CONRL4, NRL3SO2NRL4, CO, CRL1=CRL2,C≡C, SiRL1RL2, P(O)RL1, P(O)ORL1, NRL3C(═NCN)NRL4, NRL3C(═NCN),NRL3C(═CNO2)NRL4, C3-11cycloalkyl optionally substituted with 0-6 RL1and/or RL2 groups, C3-11heteocyclyl optionally substituted with 0-6 RL1and/or RL2 groups, aryl optionally substituted with 0-6 RL1 and/or RL2groups, heteroaryl optionally substituted with 0-6 RL1 and/or RL2groups; wherein RL1, RL2, RL3, RL4 and RL5 are each, independently,selected from the group consisting of H, halo, C1-8alkyl, OC1-8alkyl,SC1-8alkyl, NHC1-8alkyl, N(C1-8alkyl)2, C3-11cycloalkyl, aryl,heteroaryl, C3-11heterocyclyl, OC1-8cycloalkyl, SC1-8cycloalkyl,NHC1-8cycloalkyl, N(C1-8cycloalkyl)2, N(C1-8cycloalkyl)(C1-8alkyl), OH,NH2, SH, SO2C1-8alkyl, P(O)(OC1-8alkyl)(C1-8alkyl), P(O)(OC1-8alkyl)2,CC—C1-8alkyl, CCH, CH═CH(C1-8alkyl), C(C1-8alkyl)═CH(C1-8alkyl),C(C1-8alkyl)═C(C1-8alkyl)2, Si(OH)3, Si(C1-8alkyl)3, Si(OH)(C1-8alkyl)2,COC1-8alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5,SO2NHC1-8alkyl, SO2N(C1-8alkyl)2, SONHC1-8alkyl, SON(C1-8alkyl)2,CONHC1-8alkyl, CON(C1-8alkyl)2, N(C1-8alkyl)CONH(C1-8alkyl),N(C1-8alkyl)CON(C1-8alkyl)2, NHCONH(C1-8alkyl), NHCON(C1-8alkyl)2,NHCONH2, N(C1-8alkyl)SO2NH(C1-8alkyl), N(C1-8alkyl) SO2N(C1-8alkyl)2, NHSO2NH(C1-8alkyl), NH SO2N(C1-8alkyl)2, and NH SO2NH2; and wherein: whenq is greater than 1, RL1 or RL2 each, independently, can be linked toanother A group to form cycloalkyl and/or heterocyclyl moeity that canbe further substituted with 0-4 RL5 groups.
 17. The compound of claim 16wherein the linker group (L) is selected from the structure consistingof:

wherein: “X” is a linear chain with atoms ranging from 2 to 14 withheteroatoms optionally; and “Y” is O, N and S(O)_(n) wherein, (n=0, 1,2).
 18. The compound of claim 1, wherein the PTM group is a proteintarget moiety that binds to bromodomain-containing protein 4 (BRD4). 19.The compound of claim 18, wherein the PTM is a protein target moietythat binds to a human BET Bromodomain-containing protein is selectedfrom the structure consisting of:

wherein * indicates the point of attachment of the linker.
 20. Thecompound of claim 1, wherein the PTM is a protein target moiety selectedfrom the structure consisting of:

wherein * indicates the point of attachment of the linker.
 21. Thecompound according to claim 1, wherein the MLM comprises part ofstructural feature as in at least one of RG7112, RG7388, SAR405838,AMG-232, AM-7209, DS-5272, MK-8242, or NVP-CGM-097, and analogs orderivatives thereof.
 22. A compound is selected from the groupconsisting of chemical formula:4-(3-{4-[2-(2-{4-[2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole-1-carbonyl]piperazin-1-yl}ethoxy)ethoxy]phenyl}-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile;4-(3-{4-[(17-{4-[2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole-1-carbonyl]piperazin-1-yl}-3,6,9,12,15-pentaoxaheptadecan-1-yl)oxy]phenyl}-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile;N-(17-{[3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidin-2-yl]formamido}-3,6,9,12,15-pentaoxaheptadecan-1-yl)-2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0^(2,6)]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide;N-(2-{2-[2-(2-{[3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidin-2-yl]formamido}ethoxy)ethoxy]ethoxy}ethyl)-2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0^(2,6)]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide;N-(14-{[3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidin-2-yl]formamido}-3,6,9,12-tetraoxatetradecan-1-yl)-2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0^(2,6)]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide;3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-{2-[2-(4-{[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenoxy)ethoxy]ethyl}pyrrolidine-2-carboxamide;3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[1-(4-{[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenyl)-1,4,7,10-tetraoxadodecan-12-yl]pyrrolidine-2-carboxamide;3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-(2-{2-[2-(4-{[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenoxy)ethoxy]ethoxy}ethyl)pyrrolidine-2-carboxamide;3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[1-(4-{[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]-carbamoyl}phenyl)-1,4,7,10,13,16-hexaoxaoctadecan-18-yl]pyrrolidine-2-carboxamide;3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[1-(4-{[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenyl)-1,4,7,10,13-pentaoxapentadecan-15-yl]pyrrolidine-2-carboxamide;(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[1-(4-{[(1,3-trans)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenyl)-1,4,7,10,13-pentaoxapentadecan-15-yl]pyrrolidine-2-carboxamide;(2S,3R,4S,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[1-(4-{[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenyl)-1,4,7,10,13-pentaoxapentadecan-15-yl]pyrrolidine-2-carboxamide;3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-{4-[(2-{2-[2-(2-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0^(2,6)]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}ethoxy)ethoxy]ethoxy}ethyl)carbamoyl]-2-methoxyphenyl}-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide;3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-[4-({2-[2-(2-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0^(2,6)]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}ethoxy)ethoxy]ethyl}carbamoyl)-2-methoxyphenyl]-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide;(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-[4-({2-[2-(2-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0^(2,6)]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}ethoxy)ethoxy]ethyl}carbamoyl)-2-methoxyphenyl]-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide;(2S,3R,4S,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-[4-({2-[2-(2-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0^(2,6)]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}ethoxy)ethoxy]ethyl}carbamoyl)-2-methoxyphenyl]-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide;(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-{4-[(2-{2-[2-(2-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0^(2,6)]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}ethoxy)ethoxy]ethoxy}ethyl)carbamoyl]-2-methoxyphenyl}-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide;(2S,3R,4S,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-{4-[(2-{2-[2-(2-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0^(2,6)]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}ethoxy)ethoxy]ethoxy}ethyl)carbamoyl]-2-methoxyphenyl}-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide;3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-{4-[(14-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0^(2,6)]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}-3,6,9,12-tetraoxatetradecan-1-yl)carbamoyl]-2-methoxyphenyl}-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide;3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[4-({2-[2-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methoxy)ethoxy]ethyl}carbamoyl)-2-methoxyphenyl]pyrrolidine-2-carboxamide;3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-(4-{[2-(2-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0^(2,6)]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}ethoxy)ethyl]carbamoyl}-2-methoxyphenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide;(2S,3R,4S,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-(4-{[2-(2-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0^(2,6)]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}ethoxy)ethyl]carbamoyl}-2-methoxyphenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide;(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-(4-{[2-(2-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0^(2,6)]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}ethoxy)ethyl]carbamoyl}-2-methoxyphenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide;(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-{4-[(14-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0^(2,6)]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}-3,6,9,12-tetraoxatetradecan-1-yl)carbamoyl]-2-methoxyphenyl}-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide;(2S,3R,4S,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-N-{4-[(14-{2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0^(2,6)]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamido}-3,6,9,12-tetraoxatetradecan-1-yl)carbamoyl]-2-methoxyphenyl}-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide;3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-{4-[(1-{[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}-2,5,8,11-tetraoxatridecan-13-yl)carbamoyl]-2-methoxyphenyl}pyrrolidine-2-carboxamide;(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-{4-[(1-{[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}-2,5,8,11-tetraoxatridecan-13-yl)carbamoyl]-2-methoxyphenyl}pyrrolidine-2-carboxamide;(2S,3R,4S,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-{4-[(1-{[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}-2,5,8,11-tetraoxatridecan-13-yl)carbamoyl]-2-methoxyphenyl}pyrrolidine-2-carboxamide;(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[4-({2-[2-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methoxy)ethoxy]ethyl}carbamoyl)-2-methoxyphenyl]pyrrolidine-2-carboxamide;(2S,3R,4S,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[4-({2-[2-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methoxy)ethoxy]ethyl}carbamoyl)-2-methoxyphenyl]pyrrolidine-2-carboxamide;3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-{4-[(2-{2-[2-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methoxy)ethoxy]ethoxy}ethyl)carbamoyl]-2-ethoxyphenyl}pyrrolidine-2-carboxamide;(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-{4-[(2-{2-[2-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methoxy)ethoxy]ethoxy}ethyl)carbamoyl]-2-methoxyphenyl}pyrrolidine-2-carboxamide;(2S,3R,4S,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-{4-[(2-{2-[2-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methoxy)ethoxy]ethoxy}ethyl)carbamoyl]-2-methoxyphenyl}pyrrolidine-2-carboxamide;3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(3-{[5-(4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}phenoxy)pentyl]oxy}propyl)-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-{4-[(3-{[5-(4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}phenoxy)pentyl]oxy}propyl)carbamoyl]-2-methoxyphenyl}-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide;3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-(2-methoxy-4-{[2-(2-{[(1,4-trans)-4-({4-[1-benzyl-5-(dimethylamino)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)cyclohexyl]oxy}ethoxy)ethyl]carbamoyl}phenyl)pyrrolidine-2-carboxamide;3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[2-methoxy-5-({2-[2-(2-{[(1,4-trans)-4-({4-[1-benzyl-5-(dimethylamino)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)cyclohexyl]oxy}ethoxy)ethoxy]ethyl}carbamoyl)phenyl]pyrrolidine-2-carboxamide;3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-[4-({1-[4-(3-{[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]carbamoyl}-5-[ethyl(oxan-4-yl)amino]-4-methylphenyl)phenyl]-1,4,7,10-tetraoxadodecan-12-yl}carbamoyl)-2-methoxyphenyl]-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide;3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[2-methoxy-4-({1-[(1,4-trans)-4-({4-[1-benzyl-5-(dimethylamino)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)cyclohexyl]-1,4,7,10-tetraoxadodecan-12-yl}carbamoyl)phenyl]pyrrolidine-2-carboxamide;3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)-N-[2-methoxy-5-({1-[(1,4-trans)-4-({4-[1-benzyl-5-(dimethylamino)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)cyclohexyl]-1,4,7,10,13-pentaoxapentadecan-15-yl}carbamoyl)phenyl]pyrrolidine-2-carboxamide;and3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-[4-({1-[4-(3-{[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]carbamoyl}-5-[ethyl(oxan-4-yl)amino]-4-methylphenyl)phenyl]-1,4,7,10,13,16-hexaoxaoctadecan-18-yl}carbamoyl)-2-methoxyphenyl]-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamide,or a pharmaceutically acceptable salt, enantiomer, stereoisomer,solvate, polymorph or prodrug thereof.
 23. A composition comprising aneffective amount of the compound of claim
 1. 24. A pharmaceuticalcomposition comprising an effective amount of a compound of 1 and apharmaceutically acceptable carrier, additive, and/or excipient.
 25. Thepharmaceutical composition of 24, further comprising an additionalbioactive agent, wherein the additional bioactive agent is an anticanceragent.
 26. The composition according to 25, wherein said anticanceragent is selected from the group consisting of everolimus, trabectedin,abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152,enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763,AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, anaurora kinase inhibitor, a PIK-1 modulator, a Bcl-2 inhibitor, an HDACinhbitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an EGFRTK inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a PI3 kinaseinhibitors, an AKT inhibitor, an mTORC1/2 inhibitor, a JAK/STATinhibitor, a checkpoint-1 or 2 inhibitor, a focal adhesion kinaseinhibitor, a Map kinase kinase (mek) inhibitor, a VEGF trap antibody,pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab,amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin,ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan,tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111,131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan,IL13-PE38QQR, INO 1001, IPdR₁ KRX-0402, lucanthone, LY 317615,neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311,romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat,etoposide, gemcitabine, doxorubicin, liposomal doxorubicin,5′-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709,seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid,N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-,disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan,tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen,bevacizumab, IMC-1C11, CHIR-258,);3-[5-(methylsulfonylpiperadinemethyl)-indolylj-quinolone, vatalanib,AG-013736, AVE-0005, the acetate salt of [D-Ser(Bu t) 6, Azgly 10](pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH₂ acetate[C₅₉H₈₄N₁₈Oi₄-(C₂H₄O₂)_(x) where x=1 to 2.4], goserelin acetate,leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate,hydroxyprogesterone caproate, megestrol acetate, raloxifene,bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714;TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody,erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS-214662,tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid,valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951,aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, BacillusCalmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin,busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine,clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin,daunorubicin, diethylstilbestrol, epirubicin, fludarabine,fludrocortisone, fluoxymesterone, flutamide, gleevac, gemcitabine,hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole,lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna,methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide,oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer,procarbazine, raltitrexed, rituximab, streptozocin, teniposide,testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine,13-cis-retinoic acid, phenylalanine mustard, uracil mustard,estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosinearabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin,mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat,COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668,EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene,idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab,denileukin diftitox, gefitinib, bortezimib, paclitaxel, cremophor-freepaclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705,droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene,fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339,ZK186619, topotecan, PTK787/ZK 222584, VX-745, PD 184352, rapamycin,40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001,ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646,wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin,erythropoietin, granulocyte colony-stimulating factor, zolendronate,prednisone, cetuximab, granulocyte macrophage colony-stimulating factor,histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylatedinterferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase,lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane,alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2,megestrol, immune globulin, nitrogen mustard, methylprednisolone,ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine,bexarotene, tositumomab, arsenic trioxide, cortisone, editronate,mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase,strontium 89, casopitant, netupitant, an NK-1 receptor antagonists,palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide,lorazepam, alprazolam, haloperidol, droperidol, dronabinol,dexamethasone, methylprednisolone, prochlorperazine, granisetron,ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin,epoetin alfa, darbepoetin alfa and mixtures thereof.
 27. A method forinducing degradation of a target protein in a cell comprisingadministering an effective amount of the compound of 1 to the cell. 28.A method for treating a disease state or condition in a patient whereindysregulated protein activity is responsible for said disease state orcondition, said method comprising administering an effective amount of acompound according to claim 1, wherein the disease state or condition iscancer.
 29. The method of 28, wherein the cancer is squamous-cellcarcinoma, basal cell carcinoma, adenocarcinoma, hepatocellularcarcinomas, and renal cell carcinomas, cancer of the bladder, bowel,breast, cervix, colon, esophagus, head, kidney, liver, lung, neck,ovary, pancreas, prostate, and stomach; leukemias; benign and malignantlymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma;benign and malignant melanomas; myeloproliferative diseases; multiplemyeloma, sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi'ssarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovialsarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas,gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas,medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas,neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostatecancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer,testicular cancer, thyroid cancer, astrocytoma, esophageal cancer,pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma;carcinosarcoma, Hodgkin's disease, Wilms' tumor or teratocarcinomas,T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineage lymphoblasticLymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cell Leukemia,Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma,B-cell ALL, Philadelphia chromosome positive ALL and Philadelphiachromosome positive CML.